Search

Your search keyword '"Emma Wakeling"' showing total 104 results
Start Over Author "Emma Wakeling"
104 results on '"Emma Wakeling"'

1. Expanding the allelic spectrum of ELOVL4‐related autosomal recessive neuro‐ichthyosis

Author

Fatima Alabdulrazzaq, Talal Alanzi, Haya H. Al‐Balool, Alice Gardham, Emma Wakeling, Harry G. Leitch, Moeenaldeen AlSayed, Maha Abdulrahim, Abdulaziz Aladwani, Antonio Romito, Kapil Kampe, Sacha Ferdinandusse, Ashraf H. Aboelanine, Amira Abdullah, Amal Alwadani, Laila Bastaki, Frédéric M. Vaz, Aida M. Bertoli‐Avella, and Dana Marafi

Subjects
autosomal recessive, copy number variant, ELOVL4, neuro‐ichthyosis, Genetics, QH426-470
Abstract

Abstract Background Very long‐chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt‐like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single‐nucleotide variants. Methods We performed clinical exome sequencing on probands from four unrelated families with neuro‐ichthyosis. Results We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Conclusion Our study expands the allelic spectrum of ELOVL4‐related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

Published
2023
Full Text
View/download PDF

2. Combined novel homozygous variants in both SGPL1 and STAT1 presenting with severe combined immune deficiency: case report and literature review

Author

Adriel Roa-Bautista, Mahreen Sohail, Emma Wakeling, Kimberly C. Gilmour, Mark Davis, Anthony Gait, Giovanna Lucchini, David Cox, Reem Elfeky, and Maaike Kusters

Subjects
case report, ichthyosis, lymphopenia, steroid-resistant nephrotic syndrome (SRNS), SGPL1 gene mutation, STAT1, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundSphingosine phosphate lyase insufficiency syndrome (SPLIS) is associated with biallelic variants in SGPL1, comprising a multisystemic disease characterized by steroid resistant nephrotic syndrome, primary adrenal insufficiency, neurological problems, skin abnormalities and immunodeficiency in described cases. Signal transducer and activator of transcription 1 (STAT1) plays an important role in orchestrating an appropriate immune response through JAK-STAT pathway. Biallelic STAT1 loss of function (LOF) variants lead to STAT1 deficiency with a severe phenotype of immunodeficiency with increased frequency of infections and poor outcome if untreated.Case presentationWe report novel homozygous SGPL1 and STAT1 variants in a newborn of Gambian ethnicity with clinical features of SPLIS and severe combined immunodeficiency. The patient presented early in life with nephrotic syndrome, severe respiratory infection requiring ventilation, ichthyosis, and hearing loss, with T-cell lymphopenia. The combination of these two conditions led to severe combined immunodeficiency with inability to clear respiratory tract infections of viral, fungal, and bacterial nature, as well as severe nephrotic syndrome. The child sadly died at 6 weeks of age despite targeted treatments.ConclusionWe report the finding of two novel, homozygous variants in SGPL1 and STAT1 in a patient with a severe clinical phenotype and fatal outcome early in life. This case highlights the importance of completing the primary immunodeficiency genetic panel in full to avoid missing a second diagnosis in other patients presenting with similar severe clinical phenotype early in life. For SPLIS no curative treatment is available and more research is needed to investigate different treatment modalities. Hematopoietic stem cell transplantation (HSCT) shows promising results in patients with autosomal recessive STAT1 deficiency. For this patient’s family, identification of the dual diagnosis has important implications for future family planning. In addition, future siblings with the familial STAT1 variant can be offered curative treatment with HSCT.

Published
2023
Full Text
View/download PDF

3. Emerging phenotypes linked to variants in SAMD9 and MIRAGE syndrome

Author

Jenifer P. Suntharalingham, Miho Ishida, Ignacio Del Valle, Susanne E. Stalman, Nita Solanky, Emma Wakeling, Gudrun E. Moore, John C. Achermann, and Federica Buonocore

Subjects
SAMD9, FGR, NGS, adrenal insufficiency, endocrinopathies, myelodysplastic syndrome (MDS), Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

BackgroundHeterozygous de novo variants in SAMD9 cause MIRAGE syndrome, a complex multisystem disorder involving Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy. The range of additional clinical associations is expanding and includes disrupted placental development, poor post-natal growth and endocrine features. Increasingly, milder phenotypic features such as hypospadias in small for gestational age (SGA) boys and normal adrenal function are reported. Some children present with isolated myelodysplastic syndrome (MDS/monosomy 7) without MIRAGE features.ObjectiveWe aimed to investigate: 1) the range of reported SAMD9 variants, clinical features, and possible genotype-phenotype correlations; 2) whether SAMD9 disruption affects placental function and leads to pregnancy loss/recurrent miscarriage (RM); 3) and if pathogenic variants are associated with isolated fetal growth restriction (FGR).MethodsPublished data were analyzed, particularly reviewing position/type of variant, pregnancy, growth data, and associated endocrine features. Genetic analysis of SAMD9 was performed in products of conception (POC, n=26), RM couples, (couples n=48; individuals n=96), children with FGR (n=44), SGA (n=20), and clinical Silver-Russell Syndrome (SRS, n=8), (total n=194).ResultsTo date, SAMD9 variants are reported in 116 individuals [MDS/monosomy 7, 64 (55.2%); MIRAGE, 52 (44.8%)]. Children with MIRAGE features are increasingly reported without an adrenal phenotype (11/52, 21.2%). Infants without adrenal dysfunction were heavier at birth (median 1515 g versus 1020 g; P < 0.05) and born later (median 34.5 weeks versus 31.0; P < 0.05) compared to those with adrenal insufficiency. In MIRAGE patients, hypospadias is a common feature. Additional endocrinopathies include hypothyroidism, hypo- and hyper-glycemia, short stature and panhypopituitarism. Despite this increasing range of phenotypes, genetic analysis did not reveal any likely pathogenic variants/enrichment of specific variants in SAMD9 in the pregnancy loss/growth restriction cohorts studied.ConclusionMIRAGE syndrome is more phenotypically diverse than originally reported and includes growth restriction and multisystem features, but without adrenal insufficiency. Endocrinopathies might be overlooked or develop gradually, and may be underreported. As clinical features including FGR, severe infections, anemia and lung problems can be non-specific and are often seen in neonatal medicine, SAMD9-associated conditions may be underdiagnosed. Reaching a specific diagnosis of MIRAGE syndrome is critical for personalized management.

Published
2022
Full Text
View/download PDF

4. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome

Author

Emma Wakeling, Meriel McEntagart, Michael Bruccoleri, Charles Shaw-Smith, Karen L. Stals, Matthew Wakeling, Angela Barnicoat, Clare Beesley, Andrea K. Hanson-Kahn, Mary Kukolich, David A. Stevenson, Philippe M. Campeau, Sian Ellard, Sarah H. Elsea, Xiang-Jiao Yang, and Richard C. Caswell

Subjects
Histone deacetylase 4, intellectual disability, gain-of-function, 14-3-3 binding, Genetics, QH426-470
Abstract

Summary: Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder.

Published
2021
Full Text
View/download PDF

5. Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development

Author

Gabriella S. P. Hsia, Camila M. Musso, Lucas Alvizi, Luciano A. Brito, Gerson S. Kobayashi, Rita C. M. Pavanello, Mayana Zatz, Alice Gardham, Emma Wakeling, Roseli M. Zechi-Ceide, Debora Bertola, and Maria Rita Passos-Bueno

Subjects
acrofacial dysostosis, non-coding region, haplotype, expansion, crossing-over, Genetics, QH426-470
Abstract

Repeats in coding and non-coding regions have increasingly been associated with many human genetic disorders, such as Richieri-Costa-Pereira syndrome (RCPS). RCPS, mostly characterized by midline cleft mandible, Robin sequence and limb defects, is an autosomal-recessive acrofacial dysostosis mainly reported in Brazilian patients. This disorder is caused by decreased levels of EIF4A3, mostly due to an increased number of repeats at the EIF4A3 5′UTR. EIF4A3 5′UTR alleles are CG-rich and vary in size and organization of three types of motifs. An exclusive allelic pattern was identified among affected individuals, in which the CGCA-motif is the most prevalent, herein referred as “disease-associated CGCA-20nt motif.” The origin of the pathogenic alleles containing the disease-associated motif, as well as the functional effects of the 5′UTR motifs on EIF4A3 expression, to date, are entirely unknown. Here, we characterized 43 different EIF4A3 5′UTR alleles in a cohort of 380 unaffected individuals. We identified eight heterozygous unaffected individuals harboring the disease-associated CGCA-20nt motif and our haplotype analyses indicate that there are more than one haplotype associated with RCPS. The combined analysis of number, motif organization and haplotypic diversity, as well as the observation of two apparently distinct haplotypes associated with the disease-associated CGCA-20nt motif, suggest that the RCPS alleles might have arisen from independent unequal crossing-over events between ancient alleles at least twice. Moreover, we have shown that the number and sequence of motifs in the 5′UTR region is associated with EIF4A3 repression, which is not mediated by CpG methylation. In conclusion, this study has shown that the large number of repeats in EIF4A3 does not represent a dynamic mutation and RCPS can arise in any population harboring alleles with the CGCA-20nt motif. We also provided further evidence that EIF4A3 5′UTR is a regulatory region and the size and sequence type of the repeats at 5′UTR may contribute to clinical variability in RCPS.

Published
2018
Full Text
View/download PDF

6. Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review

Author

Saraswathy Sabanathan, Deepti Gulhane, Kshitij Mankad, James Davison, Min Tsui Ong, Rahul Phadke, Robert Robinson, Michael Spiller, Emma Wakeling, Sithara Ramdas, Angela F Brady, Meena Balasubramanian, and Pinki Munot

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Abstract

Individuals with biallelic TBCK pathogenic variants present in infancy with distinctive facial features, profound hypotonia, severe intellectual impairment and epilepsy. Although rare, it may mimic other neurogenetic disorders leading to extensive investigations. Improved understanding of the clinical phenotype can support early monitoring of complications due to respiratory insufficiency. We present six individuals who were found to have pathogenic biallelic TBCK variants. The clinico-radiological and diagnostic records were reviewed. Five individuals were diagnosed with hypoventilation, requiring respiratory support, highlighting the need for early respiratory surveillance. Characteristic brain imaging in our cohort included periventricular leukomalacia-like changes. We recommend screening for TBCK in hypotonic children with periventricular leukomalacia-like changes, particularly in the absence of prematurity.

Published
2023
Full Text
View/download PDF

10. Experiences of adolescents living with Silver-Russell syndrome

Author

Hazel Inskip, Jenny Child, Christopher D. Byrne, Angela Fenwick, Deborah J G Mackay, Elizabeth Jenkinson, I. Karen Temple, Lisa Marie Ballard, Emma Wakeling, Oluwakemi Lokulo-Sodipe, and Justin H Davies

Subjects
Male, Adolescent, media_common.quotation_subject, Emotions, Social Stigma, Pain, Stigma (botany), Dwarfism, 030209 endocrinology & metabolism, Interviews as Topic, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Adaptation, Psychological, Health care, Humans, Medicine, 030212 general & internal medicine, Fatigue, Qualitative Research, media_common, business.industry, Resilience, Psychological, Silver-Russell Syndrome, Feeling, Pediatrics, Perinatology and Child Health, Female, Psychological resilience, Thematic analysis, business, Psychosocial, Qualitative research, Clinical psychology, Adolescent health
Abstract

ObjectiveThe psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by growth failure and short stature in adulthood, has been explored in adults; however, there are no accounts of contemporary lived experience in adolescents. Such data could inform current healthcare guidance and transition to adult services. We aimed to explore the lived experience of adolescents with SRS.Design/setting/patientsIn-depth, semi-structured interviews were conducted between January 2015 and October 2016 with a sample of eight adolescents aged 13–18 (five girls) with genetically confirmed SRS from the UK. Qualitative interviews were transcribed and coded to identify similarities and differences using thematic analysis; codes were then grouped to form overarching themes.ResultsWe identified four themes from the interview data: (1) the psychosocial challenges of feeling and looking different; (2) pain, disability and fatigue; (3) anticipated stigma; and (4) building resilience and acceptance. Despite adolescents accepting SRS in their lives, they described ongoing psychosocial challenges and anticipated greater problems to come, such as stigma from prospective employers.ConclusionsAdolescents with SRS may experience psychosocial difficulties from as young as 10 years old related to feeling and looking different; pain, disability and fatigue; anticipated stigma; and future challenges around employment. We discuss these findings in relation to recommendations for the care of adolescents with SRS to prepare them for adult life.

Published
2021
Full Text
View/download PDF

11. SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Author

Reem Al-Jawahiri, Aidin Foroutan, Jennifer Kerkhof, Haley McConkey, Michael Levy, Sadegheh Haghshenas, Kathleen Rooney, Jasmin Turner, Debbie Shears, Muriel Holder, Henrietta Lefroy, Bruce Castle, Linda M. Reis, Elena V. Semina, Katherine Lachlan, Kate Chandler, Thomas Wright, Jill Clayton-Smith, Franziska Phan Hug, Nelly Pitteloud, Lucia Bartoloni, Sabine Hoffjan, Soo-Mi Park, Ajay Thankamony, Melissa Lees, Emma Wakeling, Swati Naik, Britta Hanker, Katta M. Girisha, Emanuele Agolini, Zampino Giuseppe, Ziegler Alban, Marine Tessarech, Boris Keren, Alexandra Afenjar, Christiane Zweier, Andre Reis, Thomas Smol, Yoshinori Tsurusaki, Okamoto Nobuhiko, Futoshi Sekiguchi, Naomi Tsuchida, Naomichi Matsumoto, Ikuyo Kou, Yoshiro Yonezawa, Shiro Ikegawa, Bert Callewaert, Megan Freeth, Lotte Kleinendorst, Alan Donaldson, Marielle Alders, Anne De Paepe, Bekim Sadikovic, Alisdair McNeill, Deborah Nickerson, Michael Bamshad, Suzanne Leal, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Freya Boardman-Pretty, Christopher R. Boustred, Helen Brittain, Mark J. Caulfield, Georgia C. Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, null FionaMaleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, John Pullinger, null TahrimaRahim, Augusto Rendon, null TimRogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Ana Lisa Taylor Tavares, Ellen R.A. Thomas, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Human Genetics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, and ACS - Pulmonary hypertension & thrombosis

Subjects
EXPRESSION, MUTATIONS, FEATURES, Hypogonadism, disorder, DNA Methylation, Genome sequencing, Methylation, Article, SOXC Transcription Factors, Klinefelter Syndrome, Phenotype, Neurodevelopmental disorder, Neurodevelopmental Disorders, Exome Sequencing, SOX11, Medicine and Health Sciences, Neurodevelopmental, Humans, Exome, Genetics (clinical)
Abstract

Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Published
2022

12. Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

Author

Sarah U. Morton, John Christodoulou, Gregory Costain, Francesco Muntoni, Emma Wakeling, Monica H. Wojcik, Courtney E. French, Anna Szuto, James J. Dowling, Ronald D. Cohn, F. Lucy Raymond, Basil T. Darras, David A. Williams, Sebastian Lunke, Zornitza Stark, David H. Rowitch, and Pankaj B. Agrawal

Subjects
Consensus, Intensive Care Units, Neonatal, Exome Sequencing, Infant, Newborn, Humans, Infant, Multicenter Studies as Topic, Muscle Hypotonia, Neurology (clinical), Genetic Testing, Child, Article
Abstract

IMPORTANCE: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.

Published
2022

13. BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

Author

Erin Conboy, Catherine Nowak, Karen Stals, Elliot S. Stolerman, Brett Bostwick, Tiana M. Scott, Emma Wakeling, Cyril Mignot, Sian Ellard, Brittany C. Michel, Kayla Treat, Berrak Ugur, Jill A. Rosenfeld, Caroline Nava, Sally Ann Lynch, Victoria M. Pratt, Hugo J. Bellen, Aiko Otsubo, Michael F. Wangler, Jennifer Gass, John Herriges, Jennifer B. Phillips, Gaetan Lesca, Bo Yuan, Shinya Yamamoto, Scott Barish, Marjon van Slegtenhorst, Jessica Douglas, Dihong Zhou, Patrick Edery, David R. Murdock, Jeremy Wegner, Jose Camacho, Marie Faoucher, Boris Keren, Camerun Washington, Elena Perenthaler, Kendra Engleman, Francesco Vetrini, Anita Nikoncuk, Alfredo M. Valencia, Daryl A. Scott, Cigall Kadoch, Isabelle Thiffault, Tahsin Stefan Barakat, Chun-An Chen, Lance H. Rodan, Raymond J. Louie, Hongzheng Dai, Alice S. Brooks, Nazar Mashtalir, Monte Westerfield, Nora Shannon, and Clinical Genetics

Subjects
Male, Adolescent, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Mutation, Missense, Haploinsufficiency, Article, Chromatin remodeling, 03 medical and health sciences, 0302 clinical medicine, Genetics, Animals, Drosophila Proteins, Humans, Missense mutation, Child, Zebrafish, Genetics (clinical), Genes, Dominant, 030304 developmental biology, Neurons, 0303 health sciences, Microscopy, Confocal, biology, SWI/SNF complex, Coarse facial features, Tumor Suppressor Proteins, Genetic Variation, Infant, Zebrafish Proteins, Position-effect variegation, biology.organism_classification, Phenotype, Drosophila melanogaster, Child, Preschool, Female, Neuroglia, 030217 neurology & neurosurgery, Protein Binding
Abstract

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

Published
2020
Full Text
View/download PDF

14. SILVER–RUSSELL SYNDROME

Author

Emma Wakeling

Subjects
Chromosome 7 (human), Pediatrics, medicine.medical_specialty, business.industry, Silver–Russell syndrome, Intrauterine growth restriction, medicine.disease, Maternal uniparental disomy, Speech problems, Clinical diagnosis, parasitic diseases, medicine, Imprinting (psychology), Poor postnatal growth, business
Abstract

Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face, asymmetry and feeding difficulties. As many of these features are non-specific, clinical diagnosis of SRS remains difficult. Hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 and maternal uniparental disomy (mUPD) for chromosome 7 are found in up to 60% and around 5-10% of patients with SRS, respectively. Patients with ICR1 hypomethylation are more likely to have classical features of SRS, including asymmetry; patients with mUPD7 are more likely to have learning difficulties, particularly speech problems, although these are usually mild. As features vary widely in severity, clinicians should have a low threshold for genetic investigation of patients with features suggestive of SRS.

Published
2020
Full Text
View/download PDF

15. Novel antenatal presentation of cystic hygroma in a case of Koolen-de Vries syndrome

Author

Elizabeth Oakley-Hannibal, Vipin Tyagi, Shyam Das, Emma Wakeling, and Alice Gardham

Subjects
Pregnancy, Intellectual Disability, Pediatrics, Perinatology and Child Health, Humans, Abnormalities, Multiple, Female, General Medicine, Lymphangioma, Cystic, Anatomy, Chromosome Deletion, Genetics (clinical), Pathology and Forensic Medicine, Chromosomes, Human, Pair 17
Published
2022

16. Expanding the phenotypic spectrum of ALDH18A1-related autosomal recessive cutis laxa with a description of novel neuroradiological findings

Author

Charlotte Pickwick, Bert Callewaert, Fleur van Dijk, Juliette Harris, Emma Wakeling, Eleanor Hay, Mildrid Yeo, Anupam Chakrapani, Julia Baptista, Sandra Moore, Michael Yoong, Fiona Chatterjee, and Neeti Ghali

Subjects
Pediatrics, Perinatology and Child Health, Mutation, Humans, General Medicine, Anatomy, Genetics (clinical), Cutis Laxa, Pathology and Forensic Medicine, Pedigree
Published
2021

18. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Emma Wakeling, Quan Li, Laurence E. Walsh, Maria J. Guillen Sacoto, Julie Vogt, Jeff L. Waugh, James R. Lupski, Elizabeth E. Palmer, Alan F. Rope, Robert Kleyner, Amalia Mallawaarachchi, Sebastian Lunke, Jennifer E. Posey, Pankaj B. Agrawal, Sebastien Moutton, Laurence Faivre, Zornitza Stark, Prosper Lukusa, Emily Fassi, Gareth Baynam, Gabriela Soares, Antonie D. Kline, Sonja A. de Munnik, Sarah A. Sandaradura, Chunhua Weng, Lucinda Murray, Lisa Ewans, Ganka Douglas, Eyby Leon, Shehla Mohammed, Marcia C. Willing, Elaine Marchi, Nora Alexander, Paul R. Mark, Joris Vermeesch, Lauren Dreyer, Aimé Lumaka, Koenraad Devriendt, Gholson J. Lyon, Helena Ahlfors, Katelyn Payne, Piatek G. Stefan, Jullianne Diaz, Lesley C. Adès, Simona Capponi, Jean-Baptiste Rivière, Michael F. Buckley, Amber Begtrup, H. T. Marc Timmers, Tony Roscioli, Mengge Zhao, Ana R. Gonçalves, Hanyin Cheng, Lisa Worgan, Kai Wang, and Jorge Oliveira

Subjects
Genetics, 0303 health sciences, Heart malformation, 030305 genetics & heredity, Biology, medicine.disease, Article, Hypotonia, 03 medical and health sciences, Autism spectrum disorder, Human Phenotype Ontology, Intellectual disability, medicine, Copy-number variation, Allele, medicine.symptom, Genetics (clinical), Exome sequencing, 030304 developmental biology
Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

Published
2019
Full Text
View/download PDF

19. Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

Author

Maria J. Guillen Sacoto, Jane A. Hurst, Yue Huang, Susan M. White, Michael E. March, Daniela Choukair, Qin Wang, Dana Brown, Matthew S. Kayser, Hane Lee, Tiong Yang Tan, Kristin Lindstrom, Hagit Baris Feldman, Dov Tiosano, Dong Li, Ashita Dava-Wala, Mariam Mathew, Matthew A. Deardorff, Katheryn Grand, Amy Siemon, Lynn Pais, Elizabeth J. Bhoj, Theresa Brunet, Julian A. Martinez-Agosto, Hakon Hakonarson, Naihua N. Gong, Kirsty McWalter, Claudia Gonzaga-Jauregui, Theresa A. Grebe, John Christodoulou, Melanie Brugger, Dennis Bartholomew, Yuanquan Song, Małgorzata J.M. Nowaczyk, Nikolas Boy, Emma Wakeling, Alina Kurolap, and Eva M. C. Schwaibold

Subjects
Microcephaly, animal structures, Biology, 03 medical and health sciences, fluids and secretions, 0302 clinical medicine, Neurodevelopmental disorder, Developmental Neuroscience, mental disorders, Intellectual disability, medicine, reproductive and urinary physiology, Research Articles, Loss function, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, fungi, SciAdv r-articles, Human Genetics, medicine.disease, Phenotype, ddc, Chromatin, Mushroom bodies, Sensory dendrite, 030217 neurology & neurosurgery, Research Article
Abstract

Exome sequencing and Drosophila modeling revealed variants in SMARCA5 as a novel cause of a neurodevelopmental disorder., Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

Published
2021
Full Text
View/download PDF

20. Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum

Author

Calvin Soh, Sophie Calvert, Ram L. Kumar, Isabelle Desguerre, Kevin Talbot, Evangeline Wassmer, Axel Panzer, Andrea Berger, Anna de Burca, Anu Jacob, Andrea Whitney, Andrew P. Badrock, Frances Gibbon, Shelley MacDonald, Rhys H. Thomas, Reza Maroofian, Heather Burnett, Elizabeth Jones, Thomas Blauwblomme, Francois V. Bolduc, Jamal Ghoumid, Mickaël Ferrand, Yanick J. Crow, Emma M. Jenkinson, Camilo Toro, Diana Chiang, Roseline Caumes, Gillian I. Rice, Gemma Fisher, Gopinath M. Subramanian, Edoardo Monfrini, Renaud Touraine, Hilde T. Hilmarsen, Sarju G. Mehta, Imelda Hughes, Sumit Parikh, Edward Blair, Mary O'Driscoll, Sarah Dyack, Himanshu Goel, Kristin W. Barañano, Prab Prabhakar, Luis Seabra, Roberta Battini, John H. Livingston, Russell P. Saneto, Richard J. Leventer, Katrin Õunap, Heather Marshall, Andy Cheuk Him Ng, Duccio Maria Cordelli, Natasha Demic, Daniela Neumann, Natalie Boddaert, Michael J. Noetzel, S. Richard Dunham, Ehsan Ghayoor Karimiani, Johannes A. Buckard, Frances Elmslie, Raymond T. O'Keefe, Chloe A Stutterd, Richard Sandford, Imke Metz, Francis Ramond, Liesbeth De Waele, Alessio Di Fonzo, Emma Wakeling, David B. Clifford, Crow Y.J., Marshall H., Rice G.I., Seabra L., Jenkinson E.M., Baranano K., Battini R., Berger A., Blair E., Blauwblomme T., Bolduc F., Boddaert N., Buckard J., Burnett H., Calvert S., Caumes R., Ng A.C.-H., Chiang D., Clifford D.B., Cordelli D.M., de Burca A., Demic N., Desguerre I., De Waele L., Di Fonzo A., Dunham S.R., Dyack S., Elmslie F., Ferrand M., Fisher G., Karimiani E.G., Ghoumid J., Gibbon F., Goel H., Hilmarsen H.T., Hughes I., Jacob A., Jones E.A., Kumar R., Leventer R.J., MacDonald S., Maroofian R., Mehta S.G., Metz I., Monfrini E., Neumann D., Noetzel M., O'Driscoll M., Ounap K., Panzer A., Parikh S., Prabhakar P., Ramond F., Sandford R., Saneto R., Soh C., Stutterd C.A., Subramanian G.M., Talbot K., Thomas R.H., Toro C., Touraine R., Wakeling E., Wassmer E., Whitney A., Livingston J.H., O'Keefe R.T., and Badrock A.P.

Subjects
Male, 0301 basic medicine, Proband, 030105 genetics & heredity, Gene mutation, ribosomopathy, Compound heterozygosity, Genetic analysis, Loss of heterozygosity, Leukoencephalopathy, Consanguinity, Leukoencephalopathies, Pathology, Molecular, Child, Zebrafish, Genetics (clinical), Genetics, Molecular pathology, C/D box snoRNA U8, coats plus, Labrune syndrome, leukoencephalopathy with calcifications and cysts, SNORD118, Calcinosis, Middle Aged, 3. Good health, Child, Preschool, Female, Adult, Heterozygote, Adolescent, coats plu, Biology, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, RNA, Small Nucleolar, Genetic Association Studies, Aged, leukoencephalopathy with calcifications and cyst, Infant, Newborn, Infant, medicine.disease, Disease Models, Animal, 030104 developmental biology
Abstract

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Published
2021

21. Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model

Author

Antonio Martinez-Monseny, Maddy Ashwin Reddy, Alice Gardham, Marios Kaliakatsos, L. Jeanjean, Elisabeth Rosser, Sabine Defoort, Mariona Vidal-Santacana, Nadia Giordano, Grant T. Liu, Ngozi Oluonye, Matteo Caleo, Sung Jun Ahn, Ungsoo Samuel Kim, Jinu Han, Isabelle Meunier, Michele Bertacchi, Richard Bowman, Emma Bedoukian, Gavin Arno, Patrick Yu-Wai-Man, Majida Charif, Guy Lenaers, Neringa Jurkute, Patrizia Amati-Bonneau, Andrew R. Webster, Catherine Vincent-Delorme, James Acheson, Elaine Clark, Chloé Dominici, Indran Davagnanam, Adam M Kruszewski, Graham E. Holder, Anthony G. Robson, Emma Wakeling, Robert A. Avery, Nikolas Pontikos, Chiara Tocco, Cedric Gaggioli, Michèle Studer, Jurkute, Neringa [0000-0002-3092-7451], Tocco, Chiara [0000-0002-2616-0198], Han, Jinu [0000-0002-8607-6625], Pontikos, Nikolas [0000-0003-1782-4711], Caleo, Matteo [0000-0002-4333-6378], Studer, Michèle [0000-0001-7105-2957], and Apollo - University of Cambridge Repository

Subjects
genetic structures, BBSOAS, NR2F1, inherited optic neuropathy, mouse model, optic nerve head anomalies, Optic disk, Biology, Retinal ganglion, medicine, Optic stalk, Ganglion cell layer, Retina, Optic nerve hypoplasia, AcademicSubjects/SCI01870, General Engineering, medicine.disease, eye diseases, medicine.anatomical_structure, Retinal ganglion cell, Optic nerve, Original Article, AcademicSubjects/MED00310, sense organs, Neuroscience
Abstract

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch–Boonstra–Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system., Jurkute et al. expands the phenotypic spectrum of pathogenic NR2F1 variants, providing a detailed characterization of the retinal and optic nerve changes with high-resolution optical coherence tomography imaging. Data from a mutant mouse model confirms the key role played by NR2F1 in directing retinogenesis and the development of the optic nerve head., Graphical Abstract Graphical Abstract

Published
2021
Full Text
View/download PDF

22. 127 ACTA1 associated myopathy with neurogenic EMG changes

Author

Carolynne Doherty, Julian Blake, Adnan Manzur, Emma Wakeling, Sachit Shah, Francesco Muntoni, and Mary Reilly

Subjects
Psychiatry and Mental health, Surgery, Neurology (clinical)
Abstract

BackgroundWe describe a proband and her son who have proximal limb and facial weakness and marked hand involvement. A congenital myopathy panel demonstrated two RYR1 variants and the p.Ile289Phe novel variant in ACTA1.Cases: The proband had initially been diagnosed with SMA following premature birth, late milestones, scoliosis and proximal and distal weakness which was relatively static until age 40. EMG as a child was neurogenic. Her son had poor feeding after birth, delayed motor milestones, intellectual delay, and by his teens, severe facial weakness and distal upper limb wasting particularly the finger flexors and extensors, with hip flexion of grade 3. Repeat neurophysiological evaluation of the proband at age 60, demonstrated a neurogenic pattern but also brief polyphasic motor units, raising suspicion of an addi- tional myopathic process.DiscussionZukosky and colleagues1also described a family with a different missense mutation in the ACTA1 gene who had been diagnosed with SMA on the basis of neurogenic EMG findings. Our additional family confirms that myopathy can be accompanied by neurogenic EMG changes in ACTA1 associated myopathy.Reference1. Zukosky K, Meilleur K, Traynor BJ, Dastgir J, Medne L, Devoto M, et al. Association of a Novel ACTA1 Mutation With a Dominant Progressive Scapuloperoneal Myopathy in an Extended Family. JAMA Neurol. 2015 Jun 1;72(6):689–98.carolynnedoherty@doctors.org.uk|NIHR Bursary

Published
2022
Full Text
View/download PDF

23. Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

Author

Nikolas Boy, Emma Wakeling, Julian A. Martinez, Lynn Pais, Qin Wang, Eva M. C. Schwaibold, Mariam Mathew, Katheryn Grand, Theresa Brunet, Małgorzata J.M. Nowaczyk, Matthew A Deardorff, Hane Lee, Ashita Dava-Wala, Kristin Lindstrom, Dana Brown, Kirsty McWalter, Matthew S. Kayser, Alina Kurolap, Yue Huang, Claudia Gonzaga-Jauregui, Elizabeth J. Bhoj, John Christodoulou, Hakon Hakonarson, Dov Tiosano, Amy Siemon, Tiong Yang Tan, Naihua N. Gong, Dennis Bartholomew, Yuanquan Song, Maria J. Guillen Sacoto, Hagit Baris Feldman, Dong Li, Susan M. White, Michael E. March, Daniela Choukair, Jane A. Hurst, Melanie Brugger, and Theresa A. Grebe

Subjects
Genetics, Microcephaly, Gene knockdown, Neurodevelopmental disorder, Mushroom bodies, Intellectual disability, medicine, Biology, medicine.disease, Phenotype, Loss function, Chromatin
Abstract

Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations inSMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve individuals withde novoor dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature, and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5DrosophilaorthologIswiled to smaller body size, reduced dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology and abnormal locomotor function.Iswiloss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate thatSMARCA5pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

Published
2020
Full Text
View/download PDF

24. Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood

Author

Emma Wakeling, Jenny Child, Deborah J G Mackay, Miho Ishida, Christopher D. Byrne, Justin H Davies, I. Karen Temple, Oluwakemi Lokulo-Sodipe, Hazel Inskip, Gudrun E. Moore, Angela Fenwick, and Lisa Marie Ballard

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, uniparental disomy, Short stature, Epigenesis, Genetic, Impaired glucose tolerance, Genomic Imprinting, Young Adult, Insulin-Like Growth Factor II, parasitic diseases, Genetics, medicine, Humans, Genetics (clinical), Aged, Chromosome 7 (human), business.industry, Silver Russell syndrome, Silver–Russell syndrome, Genotype-Phenotype Correlations, Retrospective cohort study, DNA Methylation, Middle Aged, medicine.disease, Uniparental disomy, Growth hormone treatment, short stature, Silver-Russell Syndrome, Phenotype, Cohort, Quality of Life, Female, RNA, Long Noncoding, medicine.symptom, imprinting, business
Abstract

BackgroundSilver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%–10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.MethodsA retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.ResultsThe median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤−2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.ConclusionHistorical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.

Published
2020

25. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome

Author

David A. Stevenson, Karen Stals, Andrea Hanson-Kahn, Sian Ellard, Michael Bruccoleri, Clare E. Beesley, Emma Wakeling, Xiang-Jiao Yang, Matthew Wakeling, Sarah H. Elsea, Philippe M. Campeau, Angela Barnicoat, Meriel McEntagart, Richard Caswell, Charles Shaw-Smith, and Mary K. Kukolich

Subjects
Genetics, gain-of-function, biology, Regulatory site, Histone deacetylase 4, QH426-470, Chromosome 2q37 Deletion Syndrome, HDAC4, Phenotype, Article, Chromatin, Histone, intellectual disability, 14-3-3 binding, biology.protein, Molecular Medicine, Missense mutation, Binding site, Genetics (clinical)
Abstract

Summary Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder., Loss-of-function variants in histone deacetylase 4 (HDAC4) have been reported to cause brachydactyly-mental retardation (BDMR) syndrome through haploinsufficiency. This report describes 7 individuals with a phenotype distinct from BDMR, all with missense variants in a conserved 14-3-3 site, which are hypothesized to result in a novel gain-of-function effect in HDAC4.

Published
2020

26. Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism

Author

Johanna Känsäkoski, Sandy Ayoub, Tiina Laine, Päivi J. Miettinen, Anna-Pauliina Iivonen, Johanna Hietamäki, Xiaonan Liu, Emma Wakeling, Louise C. Gregory, Matti Hero, Mehul T. Dattani, Nina Brandstack, Andrew J Buckton, Kirsi Vaaralahti, Markku Varjosalo, Taneli Raivio, HUS Children and Adolescents, Raivio Group, Children's Hospital, Helsinki University Hospital Area, Medicum, Department of Physiology, STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Institute of Biotechnology, Molecular Systems Biology, Helsinki Institute of Life Science HiLIFE, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, Clinicum, Centre of Excellence in Stem Cell Metabolism, Timo Pyry Juhani Otonkoski / Principal Investigator, Biosciences, and Research Programs Unit

Subjects
0301 basic medicine, Proband, Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Hypopituitarism, Sonic Hedgehog signaling, Bioinformatics, Compound heterozygosity, HORMONE DEFICIENCY, Biochemistry, NEGATIVE REGULATION, 0302 clinical medicine, Endocrinology, Sonic hedgehog, Child, Clinical Research Article, biology, CYCLE-RELATED KINASE, Prognosis, 3. Good health, Pedigree, medicine.anatomical_structure, Phenotype, Child, Preschool, FKBP8, Female, TBC1D32, AcademicSubjects/MED00250, Signal Transduction, medicine.medical_specialty, GENES, Growth hormone deficiency, 03 medical and health sciences, Anterior pituitary, Internal medicine, CILIA, medicine, Humans, retinal dystrophy, Adaptor Proteins, Signal Transducing, COMPLEX, business.industry, Biochemistry (medical), Infant, Newborn, Infant, medicine.disease, Cilium assembly, Ciliopathy, 030104 developmental biology, ciliopathy, 3121 General medicine, internal medicine and other clinical medicine, Mutation, biology.protein, PITUITARY-GLAND DEVELOPMENT, business, 030217 neurology & neurosurgery, Biomarkers, Follow-Up Studies
Abstract

Context Congenital pituitary hormone deficiencies with syndromic phenotypes and/or familial occurrence suggest genetic hypopituitarism; however, in many such patients the underlying molecular basis of the disease remains unknown. Objective To describe patients with syndromic hypopituitarism due to biallelic loss-of-function variants in TBC1D32, a gene implicated in Sonic Hedgehog (Shh) signaling. Setting Referral center. Patients A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. Interventions The patients were investigated by whole genome sequencing. Expression profiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cells followed by mass spectrometry analyses. Main Outcome Measures Genetic and phenotypic features of patients with biallelic loss-of-function mutations in TBC1D32. Results The Finnish patients harboured compound heterozygous loss-of-function variants (c.1165_1166dup p.(Gln390Phefs*32) and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Pakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variant c.1372 + 1G > A p.(Arg411_Gly458del), as did a fetus with a cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed in the developing hypothalamus, Rathke’s pouch, and areas of the hindbrain. TBC1D32 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development. Conclusions Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling.

Published
2020

27. Lived experience of Silver-Russell syndrome: implications for management during childhood and into adulthood

Author

I. Karen Temple, Deborah J G Mackay, Lisa Marie Ballard, Jenny Child, Angela Fenwick, Emma Wakeling, Justin H Davies, Hazel Inskip, Christopher D. Byrne, Elizabeth Jenkinson, and Oluwakemi Lokulo-Sodipe

Subjects
Adult, Male, Gerontology, media_common.quotation_subject, Pain, Dwarfism, Affect (psychology), Short stature, Disability Evaluation, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Multidisciplinary approach, 030225 pediatrics, Adaptation, Psychological, parasitic diseases, Health care, Humans, Psychology, Formerly Health & Social Sciences, Medicine, Russell-Silver, appearance, psychology, visible difference, growth, health, qualitative, Child, Fatigue, media_common, business.industry, Centre for Appearance Research, Lived experience, Body Height, United Kingdom, Silver-Russell Syndrome, Feeling, Pediatrics, Perinatology and Child Health, Female, medicine.symptom, business, Psychosocial, Needs Assessment, Qualitative research
Abstract

ObjectiveThere is limited information on the psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by slow growth in utero leading to short stature in adulthood. Such information could aid families in making difficult treatment decisions and guide management strategies for health professionals. We aimed to explore the lived experience of people with SRS across the lifespan.Design/setting/patientsIn-depth, semi-structured interviews were conducted between January 2015 and October 2016 with a sample of 15 adults (six women) with genetically confirmed SRS from the UK. Qualitative interviews were transcribed and coded to identify similarities and differences: codes were then grouped to form overarching themes.ResultsFour themes were identified from participant accounts: (1) appearance-related concerns extending beyond height; (2) strategies to deal with real and perceived threats; (3) women’s experiences of pain, disability and feeling older than their years; and (4) feeling overlooked in romantic relationships. These themes show that other factors, beyond short stature, affect patient well-being and indicate a mismatch between patient need and healthcare provision.ConclusionsChallenges in SRS during childhood and adolescence were central to the psychosocial impact of SRS, and were not limited to height. These challenges, as well as symptoms such as pain and fatigue for women, have not previously been documented. To help individuals with SRS develop strategies to manage psychosocial issues, we recommend clinicians incorporate psychological services as an integral part of multidisciplinary teams managing individuals with SRS during childhood, adolescence and adulthood.

Published
2018
Full Text
View/download PDF

28. Expanding the molecular basis and phenotypic spectrum of ZDHHC9 ‐associated X‐linked intellectual disability

Author

Emma Wakeling, Schaida Schirwani, Kath Smith, Ddd Study, and Meena Balasubramanian

Subjects
Male, 0301 basic medicine, Adolescent, Genotype, X-linked intellectual disability, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Child, Alleles, Genetic Association Studies, Genetics (clinical), Comparative Genomic Hybridization, Mutation, Point mutation, Macrocephaly, Facies, High-Throughput Nucleotide Sequencing, Infant, medicine.disease, Phenotype, Pedigree, 030104 developmental biology, Palpebral fissure, Mental Retardation, X-Linked, Female, medicine.symptom, Acyltransferases, 030217 neurology & neurosurgery
Abstract

Pathogenic variants in Zinc Finger DHHC-Type Containing 9 (ZDHHC9) gene have been identified as the cause of X-linked intellectual disability (XLID) in a small number of families. There are a total of 11 reported pathogenic variants in ZDHHC9 in the literature. The majority of reported variants are familial point mutations. There is one report of XLID associated with a de novo mutation in ZDHHC9, and one family with intragenic deletion within ZDHHC9 detected by array CGH. Although initial reports of families with ZDHHC9 pathogenic variants suggested a nonsyndromic XLID, more recent reports suggest a syndromic phenotype with facial dysmorphism. Here we report four patients with pathogenic variants in ZDHHC9, a family with two siblings and their maternal uncle who presented with XLID due to intragenic deletion of ZDHHC9 detected by array CGH and an 11-year-old boy with a de novo pathogenic missense variant in ZDHHC9, which is the first recurrent ZDHHC9 mutation. Our patients had some distinctive facial features in common, including elongated and down-slanting palpebral fissures and high hairline. Marfanoid habitus and seizures that have been previously reported in association with pathogenic variants in ZDHHC9 were absent in our cohort. Clinical information on patients with ZDHHC9-associated XLID is very scarce. New reports of families with detailed clinical description will add to the existing knowledge and help understand the condition better.

Published
2018
Full Text
View/download PDF

29. Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum

Author

B A Perez, C A Kim, Rachel Sayruri Honjo, R C Di Francesco, Gabriella Shih Ping Hsia, Emma Wakeling, Guilherme L. Yamamoto, Alice Gardham, Lucas Alvizi, Débora Romeo Bertola, Maria Rita Passos-Bueno, and Luiz Antônio Nunes Oliveira

Subjects
Adult, Male, 0301 basic medicine, Proband, Microcephaly, Adolescent, Genotype, Limb Deformities, Congenital, Biology, DEAD-box RNA Helicases, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Point Mutation, Allele, Child, Alleles, Genetics (clinical), DNA Repeat Expansion, Pierre Robin Syndrome, Point mutation, Dysostosis, Extremities, medicine.disease, GENÉTICA MÉDICA, Phenotype, Clubfoot, 030104 developmental biology, England, Eukaryotic Initiation Factor-4A, Female, Cleft mandible, Larynx, Hand Deformities, Congenital, Brazil
Abstract

Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.

Published
2018
Full Text
View/download PDF

30. Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing

Author

Jenny Carmichael, Emma Kivuva, Andrew E. Fry, Ravi Savarirayan, Charu Deshpande, Deirdre Cilliers, Angela F. Brady, Jacqueline Eason, Andrew Parrish, Emma L. Baple, Karen Stals, Emma Wakeling, Richard Caswell, Ruth Newbury-Ecob, Lisa Bradley, Victoria McKay, Garan Jones, Hana Lango Allen, Abhijit Dixit, Ellen Thomas, Peter D. Turnpenny, Carolyn Tysoe, Bruce Castle, Vinod Varghese, Matthew Wakeling, Adam C. Gunning, Helen Cox, Michael W. Parker, Muriel Holder, Alan Fryer, Helena Carley, Nora Shannon, Frances Elmslie, Deborah J. Shears, Sarah F. Smithson, Sian Ellard, Julia Rankin, Claire Searle, Julia Baptista, Tessa Homfray, and Pradeep Vasudevan

Subjects
0301 basic medicine, Genetics, Pregnancy, Fetus, Genetic heterogeneity, Obstetrics and Gynecology, Prenatal diagnosis, 030105 genetics & heredity, Biology, medicine.disease, Bioinformatics, Phenotype, 3. Good health, 03 medical and health sciences, 030104 developmental biology, medicine, Gene, Exome, Genetics (clinical), Exome sequencing
Abstract

Objective Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. Method Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. Results Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. Conclusion We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

Published
2017
Full Text
View/download PDF

31. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author

Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev

Subjects
Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Published
2017
Full Text
View/download PDF

32. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author

Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology

Subjects
0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Published
2017
Full Text
View/download PDF

33. Recognizing vascular Ehlers–Danlos syndrome (type IV) in the newborn

Author

Emma Wakeling, Caoimhe McKenna, Neeti Ghali, F. M. Pope, and Anthony Vandersteen

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Genotype, 030105 genetics & heredity, Pathology and Forensic Medicine, 03 medical and health sciences, Humans, Medicine, Alleles, Genetics (clinical), business.industry, Infant, Newborn, Facies, Infant, Amino acid substitution, General Medicine, medicine.disease, Infant newborn, Ehlers-Danlos syndrome type IV, Collagen Type III, Phenotype, Amino Acid Substitution, Ehlers–Danlos syndrome, Mutation, Pediatrics, Perinatology and Child Health, Ehlers-Danlos Syndrome, Anatomy, business
Published
2017
Full Text
View/download PDF

34. A novel autosomal recessive DEAF1 nonsense variant: expanding the clinical phenotype

Author

Sian Ellard, Emma Wakeling, Jogesh Kapadia, and Tala Andoni

Subjects
Male, Heterozygote, media_common.quotation_subject, Nonsense, DNA Mutational Analysis, Genes, Recessive, Consanguinity, Pathology and Forensic Medicine, Medicine, Humans, Genetic Predisposition to Disease, Pakistan, Allele, Gene, Transcription factor, Genetics (clinical), Alleles, Genetic Association Studies, media_common, Genetics, business.industry, Brain, Facies, Infant, Heterozygote advantage, General Medicine, Phenotype, Pedigree, DNA-Binding Proteins, Codon, Nonsense, Pediatrics, Perinatology and Child Health, Anatomy, business, Transcription Factors
Published
2019

35. A clinical scoring system for congenital contractural arachnodactyly

Author

Fiona Haslam McKenzie, Wouter Steyaert, Marije Koopmans, Banu Güzel Nur, Paul Coucke, Bert Callewaert, Siren Berland, Anita Rauch, Ilse Meerschaut, Florence Petit, Emma Wakeling, Edward Blair, Kathelijn Keymolen, Bernadette C. Hanna, Pascale Ribai, Shana De Coninck, Isabelle Migeotte, Frank Plasschaert, Vinod Varghese, Carina Wallgren-Pettersson, Andrew Green, Melissa Lees, Damien Lederer, Anne De Paepe, Angela Barnicoat, Irene Stolte-Dijkstra, Juliette Piard, Irene Valenzuela, Anna de Burca, Jeroen Breckpot, Franco Stanzial, Sally Ann Lynch, Iratxe Salcedo Pacheco, Ercan Mihci, Alison Male, Pradeep Vasudevan, Daniël De Wolf, Francesco Benedicenti, Cheryl Longman, Allan Bayat, Sixto García-Miñaur, Sofie Symoens, Anne Destree, Medical Genetics, and Pediatrics

Subjects
Male, Marfan syndrome, Proband, DISORDER, medicine.medical_specialty, Contracture, FIBRILLIN, PATHOGENESIS, Medical laboratory, PROBANDS, Sensitivity and Specificity, Marfan Syndrome, Diagnosis, Differential, congenital contractural arachnodactyly, 03 medical and health sciences, Arachnodactyly, Locus heterogeneity, Internal medicine, medicine, Humans, Genetics(clinical), FBN2 MUTATIONS, Genetic Testing, Congenital contractural arachnodactyly, Child, Kyphoscoliosis, fibrillin-2, Genetics (clinical), Retrospective Studies, 030304 developmental biology, 0303 health sciences, business.industry, DILATATION, 030305 genetics & heredity, Retrospective cohort study, clinical score, Sequence Analysis, DNA, Sciences bio-médicales et agricoles, medicine.disease, MARFAN-SYNDROME, 3. Good health, DELINEATION, Early Diagnosis, Phenotype, diagnostic criteria, Beals syndrome, Female, business
Abstract

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing., info:eu-repo/semantics/published

Published
2019

36. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St George’s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)

Subjects
0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019
Full Text
View/download PDF

37. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Paul R. Mark, Helena Ahlfors, Lisa Ewans, Ganka Douglas, Zornitza Stark, Lucinda Murray, Sebastian Lunke, Emily Fassi, Lauren Dreyer, Aimé Lumaka, Jullianne Diaz, Koenraad Devriendt, Lisa Worgan, Hanyin Cheng, Pankaj B. Agrawal, Laurence Faivre, H. T. Marc Timmers, Julie Vogt, Elizabeth E. Palmer, Kai Wang, Nora Alexander, Michael F. Buckley, Tony Roscioli, Chunhua Weng, Gabriela Soares, Simona Capponi, Antonie D. Kline, Jorge Oliveira, Amali Mallawaarachchi, Ana R. Gonçalves, Gareth Baynam, Eyby Leon, Marcia C. Willing, Shehla Mohammed, Sarah A. Sandaradura, Elaine Marchi, Katelyn Payne, Amber Begtrup, Piatek G. Stefan, Lesley C. Adès, Mengge Zhao, Emma Wakeling, Jean-Baptiste Rivière, Sébastien Moutton, Quan Li, Maria J. Guillen Sacoto, Jeff L. Waugh, Jennifer E. Posey, Robert Kleyner, Alan F. Rope, Prosper Lukusa, James R. Lupski, Laurence E. Walsh, Joris Vermeesch, Gholson J. Lyon, and Sonja A. de Munnik

Subjects
Genetics, TAF1, Missense mutation, Biology, Pathogenicity, Phenotype, Genetics (clinical)
Published
2020
Full Text
View/download PDF

38. PEHO syndrome: the endpoint of different genetic epilepsies

Author

Mohnish Suri, Hamish Houston, Alasdair Parker, C. Geoffrey Woods, Sameer M. Zuberi, Manali Chitre, Michael S. Nahorski, Angela F. Brady, Kaitlin Stouffer, Bryony Dunning-Davies, Emma Wakeling, Woods, C Geoffrey [0000-0002-8077-2101], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Candidate gene, medicine.medical_specialty, Neurology, Genotype, Brain Edema, Bioinformatics, epilepsy and seizures, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine, developmental, Humans, PEHO syndrome, genetics, Genetic Predisposition to Disease, Genetic Testing, Genetics (clinical), Exome sequencing, Alleles, Genetic Association Studies, Epilepsy, business.industry, Genetic heterogeneity, neurology, Age Factors, Infant, Newborn, Facies, Infant, Electroencephalography, Neurodegenerative Diseases, medicine.disease, Magnetic Resonance Imaging, Hypsarrhythmia, Pedigree, Optic Atrophy, 030104 developmental biology, Phenotype, Child, Preschool, Mutation, Etiology, Female, medicine.symptom, business, Spasms, Infantile, 030217 neurology & neurosurgery, Biomarkers
Abstract

BackgroundProgressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder.MethodChildren with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra–interfamilial phenotypic correlations and genotype–phenotype correlations when pathological mutations were identified.ResultsTwenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl’s DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes.ConclusionsWe found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities—and are phenotypic endpoints of many severe genetic encephalopathies.

Published
2018

39. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care

Subjects
0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Published
2018
Full Text
View/download PDF

40. The phenotype and cardio-metabolic associations of Silver-Russell syndrome in an older cohort and the effects of childhood growth hormone treatment

Author

Oluwakemi Lokulo-Sodipe, Hazel M Inskip, Jenny Child, Christopher D. Byrne, Temple I Karen, Deborah J G Mackay, Emma Wakeling, and Justin H Davies

Subjects
Childhood growth, Cardio metabolic, business.industry, Silver–Russell syndrome, Cohort, Physiology, Medicine, business, medicine.disease, Phenotype, Hormone
Published
2018
Full Text
View/download PDF

41. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author

Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology

Subjects
0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published

Published
2018
Full Text
View/download PDF

42. A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication

Author

Richard Keen, Emma Wakeling, Tracy Lester, Helen Lord, Mike G. Harrison, Amina Al-Yassin, Michael Oldridge, Alistair Calder, and Sophie Watkins

Subjects
0301 basic medicine, Adult, Male, Maxillary hypoplasia, Core Binding Factor Alpha 1 Subunit, Osteochondrodysplasias, Short stature, Article, 03 medical and health sciences, 0302 clinical medicine, Jaw Abnormalities, Gene Duplication, Gene duplication, Genetics, medicine, Humans, Genetics (clinical), Aged, business.industry, Tooth Abnormalities, Metaphyseal flaring, Brachydactyly, Anatomy, Syndrome, Middle Aged, medicine.disease, Metaphyseal dysplasia, Pedigree, 030104 developmental biology, Dysplasia, Female, Tandem exon duplication, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis. To date, only one large French Canadian family and a Finnish woman have been reported with the condition. In both, intragenic duplication encompassing exons 3–5 of the RUNX2 gene was identified. We describe a new, three-generation family with clinical features of MDMHB and an intragenic tandem duplication of RUNX2 exons 3–6. Dental problems were the primary presenting feature in all four affected individuals. We compare the features in our family to those previously reported in MDMHB, review the natural history of this condition and highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies.

Published
2018

43. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

Author

Rolph Pfundt, Sarju G. Mehta, Amy Lawson Yuen, Gunnar Houge, Marie-Cécile Nassogne, Nicola S. Cooper, Bjørn Ivar Haukanes, Ingvild Aukrust, Siren Berland, Pradeep Vasudevan, Mónica Roselló, Stéphanie Moortgat, Nina Powell-Hamilton, Charlotte von der Lippe, Barbara van Loon, Ruth Newbury-Ecob, Alain Verloes, Laura A. Baker, Trine Prescott, Andrew O.M. Wilkie, Emma Wakeling, Ddd Study, Isabelle Maystadt, Francisco Martínez, Laurence Faivre, Alfonso Caro-Llopis, Karen J. Low, Emma Kivuva, François-Guillaume Debray, Thatjana Gardeitchik, Louise C. Wilson, Christine Verellen-Dumoulin, Valérie Benoit, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie pédiatrique

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, X-linked intellectual disability, Ubiquitin-Protein Ligases, Mutation, Missense, Short stature, Article, Craniosynostosis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Intellectual Disability, Intellectual disability, Obligate carrier, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), X chromosome, Genes, Dominant, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Tumor Suppressor Proteins, Genetic Diseases, X-Linked, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Dermatology, 030104 developmental biology, Speech delay, Female, medicine.symptom, business
Abstract

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

Published
2018

44. A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype

Author

Jill Clayton-Smith, Mariet W. Elting, Rutger A.J. Nievelstein, Linda Goodwin, Andreas Zankl, Paul Coucke, Paulien A. Terhal, Susan Price, Anne Dieux, Valérie Cormier-Daire, Eva J J Verver, Louise C. Wilson, Edward S. Tobias, Sahar Mansour, Niels Thomas Hertel, Maaike Vreeburg, Johanna C. Herkert, Emma Wakeling, Nicolette S. den Hollander, Elizabeth Thompson, Bronwyn Kerr, Marleen Simon, Nine V A M Knoers, Hanne Hove, Mohnish Suri, Tessa Homfray, Frances Elmslie, Raoul C.M. Hennekam, Muriel Holder-Espinasse, Jane A. Hurst, Sarah F. Smithson, André Mégarbané, Yasemin Alanay, Melissa Lees, Vedat Topsakal, Annick Raas-Rothschild, Marianne Rohrbach, Allan M. Lund, Barbara Schroeter, Hermine E. Veenstra-Knol, Regina C. Betz, Johanna M. van Hagen, Annick Toutain, Geert Mortier, Paula van Dommelen, Alison Male, Andrew Green, Kristien Hoornaert, Ernie M.H.F. Bongers, Annemarie H. van der Hout, Albert David, Goeran Anneren, Martine Le Merrer, Jenneke van den Ende, Esther Kinning, Carlo Marcelis, Surgical clinical sciences, Ear, nose & throat, Acibadem University Dspace, Clinical Genetics, Human genetics, Other Research, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Human Genetics

Subjects
Male, Hypermetropia, DNA Mutational Analysis, Review, Gene, Osteochondrodysplasias/congenital, Spondyloepiphyseal dysplasia, Genetics(clinical), Child, SEDC, COL2A1 gene, Bronchomalacia, Atlantoaxial dislocation, Pierre Robin syndrome, Osteotomy, Scoliosis, Health, Cleft palate, Spondyloepiphyseal dysplasia congenita, II COLLAGEN, Cohort studies, Hip arthroplasty, SKELETAL DYSPLASIA, Procollagen, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, COL2A1, Glycine, Major clinical study, Osteochondrodysplasias, Behavioural Changes, SDG 3 - Good Health and Well-being, Genetics, spondyloepiphyseal dysplasia, Humans, Genotype phenotype correlation, Collagen Type II, Aged, Tracheomalacia, Infant, medicine.disease, Otorhinolaryngology, DEFECT, Collagen disorder, School child, Human medicine, mutation, MYELOPATHY, Pediatrics, Amino acid substitution, Spondyloperipheral dysplasia, LS - Life Style, surgery, Tracheostomy, Serine, Myopia, Missense mutation, RETINAL-DETACHMENT, Non-U.S. Gov't, Genetics (clinical), Heterozygosity, Research Support, Non-U.S. Gov't, Odontoid Hypoplasia, Middle Aged, genotype-phenotype, Clubfoot, Phenotype, KNIEST-DYSPLASIA, young adult, Female, medicine.symptom, Collagen Type II/genetics, Healthy Living, radiography, Adult, EXPRESSION, Retina detachment, Child, preschool, Adolescent, review, Population research, Genotype-phenotype, Research Support, Short stature, Hearing impairment, Multiple epiphyseal dysplasia, Kniest dysplasia, CARTILAGE, Coxa vara, Journal Article, medicine, Gene mutation, Disease severity, Genetic Association Studies, business.industry, Gestational age, Respiratory distress, Mutational analysis, GENE, Clinical feature, Dysplasia, Aspartic acid, ELSS - Earth, Life and Social Sciences, Healthy for Life, business
Abstract

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders. (c) 2015 Wiley Periodicals, Inc.

Published
2015
Full Text
View/download PDF

45. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author

Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles

Subjects
0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Published
2017
Full Text
View/download PDF

46. Heterozygous mutations affecting the protein kinase domain of

Author

Mark J, Hamilton, Richard C, Caswell, Natalie, Canham, Trevor, Cole, Helen V, Firth, Nicola, Foulds, Ketil, Heimdal, Emma, Hobson, Gunnar, Houge, Shelagh, Joss, Dhavendra, Kumar, Anne Katrin, Lampe, Isabelle, Maystadt, Victoria, McKay, Kay, Metcalfe, Ruth, Newbury-Ecob, Soo-Mi, Park, Leema, Robert, Cecilie F, Rustad, Emma, Wakeling, Andrew O M, Wilkie, The Deciphering Developmental Disorders, Study, Stephen R F, Twigg, and Mohnish, Suri

Subjects
Male, Models, Molecular, Heterozygote, protein kinases, Adolescent, Developmental Disabilities, Mutation, Missense, Syndrome, congenital heart defects, Protein Domains, cdk13, Intellectual Disability, CDC2 Protein Kinase, Mutation, Humans, Thermodynamics, Female, New Disease Loci, Child, exome sequencing, Conserved Sequence, ohdo syndrome
Abstract

Introduction Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. Methods Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. Results Our cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. Conclusions These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

Published
2017

47. Corrigendum: Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author

Rosaline Caumes, Andrea Berger, John Stone, Roberta Battini, Charles Marques Lourenço, Gerardine Quaghebeur, Nicholas A. Fletcher, Elliott H. Sherr, Marjo S. van der Knaap, Sanjeev S. Bhaskar, Marco Henneke, Kanaga R. Sinnathuray, Pierre Landrieu, James O'Sullivan, Calvin Soh, Himanshu Goel, Patrick Ferreira, Katrin Õunap, Cheryl Hemingway, Laurence C. Goosey, Graham D. Pavitt, Hilde Van Esch, Prab Prabhakar, Yoann Rose, Jill E. Urquhart, Yanick J. Crow, Gabriela M. Baerlocher, Simon G. Williams, Mathieu P Rodero, Ram L. Kumar, Emma M. Jenkinson, Gillian I. Rice, Sarju G. Mehta, Adeline Vanderver, Timothy J. Malpas, Christopher J. Kershaw, Imke Metz, Edward Blair, Paul R. Kasher, Imelda Hughes, Patrick Revy, David Cassiman, Duccio Maria Cordelli, Angela Barnicoat, Andrea Whitney, Janice E. Brunstrom-Hernandez, Axel Panzer, Kristin W. Barañano, Liesbeth De Waele, Geraldine Aubert, Raphael Schiffmann, H. Stewart, Monika Haubitz, Rosalind J. Jefferson, Alan Fryer, Anthony Oojageer, Carolina Uggenti, John H. Livingston, Sam Griffiths-Jones, Christine E. G. van Mol, Johannes A. Buckard, Raymond T. O'Keefe, Lieven Lagae, Emma Wakeling, Sakkubai Naidu, Alex J. Fay, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Department of Medical Genetics, and HMNC Brain Health

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Biology, medicine.disease, Article, 3. Good health, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Cerebral microangiopathy, Genetics, medicine, 610 Medicine & health, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Published
2017
Full Text
View/download PDF

48. Diagnosis and management of Silver-Russell syndrome: first international consensus statement

Author

Frédéric Brioude, I. Karen Temple, Jet Bliek, Adda Grimberg, Thomas Eggermann, Gudrun E. Moore, Agnès Linglart, Klaus Mohnike, Zeynep Tümer, Edith Said, Ana Pinheiro Machado Canton, Renuka P Dias, Oluwakemi Lokulo-Sodipe, Madeleine D. Harbison, Meropi Toumba, Gerhard Binder, Béatrice Dubern, Anita C. S. Hokken-Koelega, Jennifer Salem, Deborah J G Mackay, Susan M. O’Connell, Miriam Elbracht, Irène Netchine, Justin H Davies, David Monk, Silvia Russo, Emma Wakeling, Mohamad Maghnie, Isabelle Oliver Petit, Krystyna H. Chrzanowska, Eloise Giabicani, Philip Murray, Masayo Kagami, Alexander A. L. Jorge, Tsutomu Ogata, Karen Grønskov, Pediatrics, North West london hospitals NHS Trust, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MAGIC Foundation, Department of Clinical Genetics, University of Amsterdam [Amsterdam] (UvA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Clinical genetic clinic, Copenhagen University Hospital, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Service d'endocrinologie pédiatrique [CHU Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fetal Growth and Developmental Group, University College of London [London] (UCL), Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Department of Pediatrics and Medical Genetics, St. Luke's Hospital, Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Human Genetics and Genomic Medicine group, Faculty of Medicine, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Human Genetics

Subjects
0301 basic medicine, medicine.medical_specialty, Pediatrics, Internationality, Endocrinology, Diabetes and Metabolism, Gonadotropin-Releasing Hormone/therapeutic use, Human Growth Hormone/therapeutic use, MESH: Disease Management, law.invention, Gonadotropin-Releasing Hormone, 03 medical and health sciences, Endocrinology, Randomized controlled trial, law, Internal medicine, MESH: Gonadotropin-Releasing Hormone, medicine, MESH: Human Growth Hormone, Humans, Silver-Russell Syndrome/diagnosis, Motor skill, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, Human Growth Hormone, business.industry, Adrenarche, Disease Management, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Diabetes and Metabolism, Growth hormone treatment, Natural history, Silver-Russell Syndrome, 030104 developmental biology, MESH: Silver-Russell Syndrome, Speech delay, MESH: Internationality, Small for gestational age, medicine.symptom, business, Psychosocial
Abstract

International audience; This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

Published
2017
Full Text
View/download PDF

49. Baseline and post prophylactic tubal–ovarian surgery CA125 levels in BRCA1 and BRCA2 mutation carriers

Author

Emma Wakeling, Sibel Saya, Susan Shanley, Sue Ashley, Ying Chen, Rosalind A. Eeles, Elizabeth Bancroft, Sarah Thomas, and Audrey Arden-Jones

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, Ovariectomy, Genes, BRCA2, Genes, BRCA1, Salpingectomy, Young Adult, Internal medicine, Genetics, medicine, Fallopian Tube Neoplasms, Humans, Genetic Predisposition to Disease, Young adult, skin and connective tissue diseases, Predictive testing, Genetics (clinical), Aged, Retrospective Studies, Ovarian Neoplasms, Gynecology, business.industry, BRCA mutation, Retrospective cohort study, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, Discontinuation, CA-125 Antigen, Population Surveillance, Mutation, Mutation (genetic algorithm), Female, Histopathology, Ovarian cancer, business
Abstract

The aim of this study was to determine whether BRCA1 and BRCA2 mutation carriers have different baseline CA125 levels compared with non-carriers, and whether a significant difference in pre- and post-operative CA125 levels exists in BRCA mutation carriers undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). The study also considered whether CA125 measurements should continue in unaffected BRCA mutation carriers after RRBSO. 383 Eligible women were identified through retrospective review of the BRCA Carrier Clinic at The Royal Marsden NHS Foundation Trust, London, UK. These women all had CA125 levels measured as they were either a carrier or at risk of a BRCA1 or BRCA2 mutation. Of these, 76 went on to have a negative predictive test for their familial mutation and so are classed as 'non-carriers'. 133 BRCA1 and 87 BRCA2 carriers had RRBSO, with a further 26 BRCA1 carriers, 28 BRCA2 carriers and one non-carrier developing ovarian cancer. The remaining 21 BRCA1 and 28 BRCA2 carriers did not have RRBSO or develop ovarian cancer in the time of study follow-up. CA125 levels were measured as surveillance or as part of pre-RRBSO care. CA125 measurement post-RRBSO was continued in 48 BRCA1 and 40 BRCA2 carriers. In 154 BRCA1 mutation carriers, the median baseline (i.e. before RRBSO and with no clinical signs of ovarian cancer) CA125 level was 9.0 U/ml (range 2-78) and was 10.0 U/ml (range 1-43) in 115 BRCA2 mutation carriers. When compared with the 75 non-carriers (median baseline CA125 10.0 U/ml; range 2-52), there was no significant difference between the BRCA1, BRCA2 and non-carrier groups. There was a significant reduction in CA125 from pre- to post-RRBSO in 48 BRCA1 carriers (p = 0.04) but no significant difference in 40 BRCA2 mutation carriers (p = 0.5). Out of a total of 220 mutation carriers who underwent RRBSO, two had an incidental ovarian cancer found on histopathology and another developed primary peritoneal cancer during the follow-up period. Our study is the first to compare initial serum CA125 levels in BRCA1 and BRCA2 mutation carriers with those of non-carriers. Our study found no significant difference between the three groups. A drop in CA125 levels after RRBSO in BRCA1 carriers supports the finding of earlier studies, but differed in that the fall was not seen in BRCA2 carriers. The finding of only one case of post-operative peritoneal cancer in 220 carriers undergoing RRBSO supports the discontinuation of post-RRBSO serum CA125 monitoring in BRCA mutation carriers.

Published
2014
Full Text
View/download PDF

50. Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome

Author

Soo-Mi Park, Deciphering Developmental Disorders Study, Morad Ansari, James D.P. Rhodes, Alison Ross, Emma Wakeling, Nicola Carroll, Ana Blatnik, Fiona Stewart, Hemant Bengani, Graeme R. Grimes, Madapura M. Pradeepa, David R. FitzPatrick, Gabrielle Olley, Alex von Kriegsheim, and Wendy A. Bickmore

Subjects
0301 basic medicine, Genetics, 03 medical and health sciences, 030104 developmental biology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, NIPBL, 010501 environmental sciences, Biology, 01 natural sciences, 0105 earth and related environmental sciences
Abstract

In the version of this article initially published, Wendy Bickmore and Madapura Pradeepa were incorrectly not indicated as corresponding authors. The error has been corrected in the HTML and PDF versions of the paper.

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results