43 results on '"Natalie Hauser"'
Search Results
2. Endosomal trafficking defects in patient cells with KIAA1109 biallelic variants
- Author
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Megan S. Kane, Callie J. Diamonstein, Natalie Hauser, John F. Deeken, John E. Niederhuber, and Thierry Vilboux
- Subjects
Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
The uncharacterized gene KIAA1109 has recently been associated with a congenital neurological malformation disorder that variably presents with arthrogryposis, craniofacial and/or cardiac abnormalities. We have identified two additional patients with compound heterozygous KIAA1109 variants presenting with the same neurological malformations. The mechanism whereby KIAA1109 loss of function causes this spectrum of disorders was the primary focus of our studies. We hypothesized that KIAA1109 function could be conserved relative to the fly gene tweek and examined endocytosis and endosome recycling in patient fibroblasts. Furthermore, we examined the structure of the cytoskeleton and cilia based on functional overlap with endocytosis and several known etiologies for neuronal migration disorders. Utilizing primary dermal fibroblasts from one patient and a healthy donor, we performed immunofluorescence and endocytosis assays to examine the endosomal, cytoskeletal, and ciliary cellular phenotypes. We found notable abnormalities in endosomal trafficking and endosome recycling pathways. We also observed changes in the actin cytoskeleton and cilia structural dynamics. We conclude that the function of KIAA1109 in humans may indeed overlap with the function of the Drosophila ortholog, resulting in perturbations to endosomal trafficking and the actin cytoskeleton. These alterations have ripple effects, altering many pathways that are critical for proper neuronal migration and embryonic development. Keywords: Cilia, Endocytosis, KIAA1109, Neurological malformation, Vesicular trafficking
- Published
- 2019
- Full Text
- View/download PDF
3. Diagnosis of LCHAD/TFP deficiency in an at risk newborn using umbilical cord blood acylcarnitine analysis
- Author
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Donna B. Raval, Kristina P. Cusmano-Ozog, Omar Ayyub, Callie Jenevein, Laura H. Kofman, Brendan Lanpher, Natalie Hauser, and Debra S. Regier
- Subjects
LCHAD ,Long-chain hydroxyacyl-CoA dehydrogenase deficiency ,Umbilical cord blood ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency.
- Published
- 2017
- Full Text
- View/download PDF
4. Expanding the phenotype of <scp> ASXL3 </scp> ‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in <scp> ASXL3 </scp>
- Author
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Katherine Bergstrom, Nichola Foulds, Yue Si, Anne Slavotinek, John Dean, Evan Reid, Ruth Armstrong, Charlotte W. Ockeloen, Richard Fisher, Maria J. Guillen Sacoto, Dayna Morel, Fowzan S. Alkuraya, Costa Cinzia, Thomas D. Challman, Samantha A. Schrier Vergano, Francisca Milan Zamora, Naomi Meeks, John Pappas, Katheryn Grand, Abhijit Dixit, Julie S. Cohen, Ddd Study, Marjolein H. Willemsen, Serwet Demirdas, Rachel Harrison, Usha Kini, Bertrand Isidor, Patricia Blanchet, Emily Palen, Arjan Bouman, Jagdeep S. Walia, Ruth Newbury-Ecob, Rachel Rabin, Shadi Albaba, Diana Johnson, Paolo Prontera, Paula Girotto, Ange-Line Bruel, Meena Balasubramanian, Nicola K. Ragge, Schaida Schirwani, Deborah L. Renaud, Christopher Cunniff, John M. Graham, Natalie Dykzeul, Swati Naik, Valerie Slegesky, Hessa F Albassam, Maria Giovanna Tedesco, Sally Ann Lynch, Julie Vogt, Natalie Hauser, Dong Li, Deanna Alexis Carere, and Benjamin Cogné
- Subjects
Genetics ,Biology ,medicine.disease ,Phenotype ,Hypotonia ,Natural history ,Neurodevelopmental disorder ,Intellectual disability ,medicine ,Missense mutation ,Hypertelorism ,medicine.symptom ,Genetics (clinical) ,Sequence (medicine) - Abstract
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
- Published
- 2021
5. Novel HIVEP2 pathogenic variant in a patient with rapid, severe brain atrophy. Second condition, or expansion of the phenotype?
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Natalie Hauser
- Subjects
Pathology ,medicine.medical_specialty ,Endocrinology ,Atrophy ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,medicine ,medicine.disease ,business ,Molecular Biology ,Biochemistry ,Phenotype - Published
- 2021
6. Predominant and novel de novo variants in 29 individuals with <scp> ALG13 </scp> deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions
- Author
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Hudson H. Freeze, Deborah A. Nickerson, Pengfei Liu, Eva Morava, Lynne A. Wolfe, Raymond Y. Wang, Dorcas Wilson, Sergey A. Shiryaev, Yin Y Dong, Janice Cousin, Michael A. Ciliberto, C. G. Asteggiano, Gabriela Magali Papazoglu, Katherine Hammond, Alice Zalan, Timothy Blake Palculict, Kimberly M Houck, Jennefer N. Kohler, Richard Webster, Ingrid E. Scheffer, William D. Graf, John Christodoulou, Bobby G. Ng, Wendy K. Chung, Colleen E. McCormack, Austin Larson, Rossana Sanchez Russo, Fiona Gardiner, Jonathan A. Bernstein, Beth A. Pletcher, Farouq Thabet, Rhonda E. Schnur, Leah J. Rowe, Yue Si, María Mercedes Villanueva, Eileen Barr, Natalie Hauser, Erik A. Eklund, Alvaro H Serrano Russi, Rebecca Miller, Stephanie Grunewald, Andrea Schenone, Allysa Tuite, Suman Ghosh, Jill A. Rosenfeld, Mary-Alice Abbott, Sujana Madathil, Lindsay Rhodes, Shabeed Chelakkadan, Michael J. Bamshad, Naomi Meeks, George E. Hoganson, and Kristin G. Monaghan
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Glycosylation ,medicine.medical_treatment ,Biology ,N-Acetylglucosaminyltransferases ,Article ,purl.org/becyt/ford/1 [https] ,chemistry.chemical_compound ,Congenital Disorders of Glycosylation ,N-linked glycosylation ,N-LINKED GLYCOSYLATION ,Genetics ,medicine ,Humans ,CONGENITAL DISORDERS OF GLYCOSYLATION ,purl.org/becyt/ford/1.6 [https] ,EPILEPSY ,Genetics (clinical) ,Exome sequencing ,Transferrin ,Infant ,medicine.disease ,WHOLE EXOME SEQUENCING ,Epileptic spasms ,Uridine diphosphate ,chemistry ,Child, Preschool ,Mutation ,Medical genetics ,Female ,Diet, Ketogenic ,Spasms, Infantile ,Congenital disorder of glycosylation ,Biomarkers ,Ketogenic diet - Abstract
Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals. Fil: Ng, Bobby G.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos Fil: Eklund, Erik A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos. Lund University; Suecia Fil: Shiryaev, Sergey A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos Fil: Dong, Yin Y.. University of Oxford; Reino Unido Fil: Abbott, Mary Alice. University of Massachusetts Medical School; Estados Unidos Fil: Asteggiano, Carla Gabriela. Universidad Católica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Bamshad, Michael J.. University of Washington; Estados Unidos Fil: Barr, Eileen. University of Emory; Estados Unidos Fil: Bernstein, Jonathan A.. University of Stanford; Estados Unidos Fil: Chelakkadan, Shabeed. Monash Children's Hospital; Australia Fil: Christodoulou, John. Sydney Medical School; Australia. University of Melbourne; Australia Fil: Chung, Wendy K.. Columbia University; Estados Unidos Fil: Ciliberto, Michael A.. University of Iowa; Estados Unidos Fil: Cousin, Janice. National Human Genome Research Institute ; Estados Unidos Fil: Gardiner, Fiona. University of Melbourne; Australia Fil: Ghosh, Suman. University of Florida; Estados Unidos Fil: Graf, William D.. University of Connecticut; Estados Unidos Fil: Grunewald, Stephanie. University College London; Estados Unidos Fil: Hammond, Katherine. University of Alabama at Birmingahm; Estados Unidos Fil: Hauser, Natalie S.. Inova, Fairfax Hospital Falls Church; Estados Unidos Fil: Hoganson, George E.. University Of Illinois At Chicago; Estados Unidos Fil: Houck, Kimberly M.. Baylor College of Medicine; Estados Unidos Fil: Kohler, Jennefer N.. University of Stanford; Estados Unidos Fil: Morava, Eva. Mayo Clinic; Estados Unidos Fil: Larson, Austin A.. University Of Colorado Anschutz Medical Campus.; Estados Unidos Fil: Liu, Pengfei. Baylor Genetics; Estados Unidos. Baylor College Of Medicine; Estados Unidos Fil: Madathil, Sujana. University of Iowa; Estados Unidos Fil: McCormack, Colleen. University of Stanford; Estados Unidos Fil: Meeks, Naomi J.L.. University Of Colorado Anschutz Medical Campus.; Estados Unidos Fil: Papazoglu, Gabriela Magali. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
- Published
- 2020
7. Pitfalls of clinical exome and gene panel testing: alternative transcripts
- Author
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Prachi Kothiyal, Dale L. Bodian, and Natalie Hauser
- Subjects
0301 basic medicine ,Computational biology ,030105 genetics & heredity ,Biology ,medicine.disease ,Genome ,Human genetics ,03 medical and health sciences ,Exon ,Epilepsy ,030104 developmental biology ,medicine ,Coding region ,Gene ,Exome ,Genetics (clinical) ,Exome sequencing - Abstract
Clinical exome and gene panel testing can provide molecular diagnoses for patients with rare Mendelian disorders, but for many patients these tests are nonexplanatory. We investigated whether interrogation of alternative transcripts in known disease genes could provide answers for additional patients. We integrated alternative transcripts for known neonatal epilepsy genes with RNA-Seq data to identify brain-expressed coding regions that are not evaluated by popular neonatal epilepsy clinical gene panel and exome tests. We found brain-expressed alternative coding regions in 89 (30%) of 292 neonatal epilepsy genes. The 147 regions encompass 15,713 bases that are noncoding in the primary transcripts analyzed by the clinical tests. Alternative coding regions from at least 5 genes carry reported pathogenic variants. Three candidate variants in these regions were identified in public exome data from 337 epilepsy patients. Incorporating alternative transcripts into the analysis of neonatal epilepsy genes in 44 patient genomes identified the pathogenic variant for the epilepsy case and 2 variants of uncertain significance (VUS) among the 43 control cases. Assessment of alternative transcripts in exon-based clinical genetic tests, including gene panel, exome, and genome sequencing, may provide diagnoses for patients for whom standard testing is unrevealing, without introducing many VUS.
- Published
- 2019
8. Genotype-first analysis of a generally healthy population cohort supports genetic testing for diagnosis of hereditary angioedema of unknown cause
- Author
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Natalie Hauser, Thierry Vilboux, and Dale L. Bodian
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Genetic testing ,PLG ,Case Report ,C1-inhibitor ,Diagnostic yield ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Medical history ,Angioedema ,Clinical sequencing ,Hereditary angioedema ,medicine.diagnostic_test ,biology ,Nextgen sequencing ,business.industry ,Plasminogen ,General Medicine ,medicine.disease ,Personalized medicine ,Dermatology ,3. Good health ,030104 developmental biology ,030228 respiratory system ,Cohort ,biology.protein ,Etiology ,Differential diagnosis ,medicine.symptom ,business ,lcsh:RC581-607 - Abstract
Background Hereditary angioedema (HAE) is a potentially life-threatening group of conditions that is often underdiagnosed or misdiagnosed. As HAE is typically diagnosed by detecting C1 inhibitor deficiency, there is a critical need for methods that can identify affected individuals with normal C1 inhibitor. The recent discovery of associations between PLG K330E and ANGPT1 A119S and HAE of unknown genetic cause (HAE-U), has raised the possibility that genetic evaluation could be used to diagnose HAE-U in patients with unexplained angioedema or non-confirmatory laboratory testing. Case presentation We analyzed genome sequences from a generally healthy population cohort of 2820 adults and identified PLG K330E in one individual. Subsequent review of this participant’s medical history revealed symptoms clinically attributed to allergy of unknown etiology but that are consistent with published descriptions of HAE patients carrying the PLG K330E variant. The participant, a 31 year old female, reported lip and tongue angioedema, without wheals, which did not respond to treatment with steroids or antihistamines. Conclusions The genotype-first approach demonstrated that detection of PLG K330E in undiagnosed or misdiagnosed individuals can identify patients actually affected with HAE-U. The genetic diagnosis will facilitate selection of appropriate treatment, discontinuation of therapies ineffective for this condition, and timely diagnosis of affected family members. The results support a role of PLG K330E in the pathogenesis of HAE and suggest that genetic testing be considered as an approach to diagnose patients with unexplained angioedema.
- Published
- 2019
9. Endosomal trafficking defects in patient cells with KIAA1109 biallelic variants
- Author
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Thierry Vilboux, Natalie Hauser, John E. Niederhuber, John F. Deeken, Megan S. Kane, and Callie J. Diamonstein
- Subjects
lcsh:QH426-470 ,Endosome ,Neurological malformation ,Biology ,Endocytosis ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,KIAA1109 ,Cilia ,Cytoskeleton ,Molecular Biology ,Genetics (clinical) ,Loss function ,030304 developmental biology ,0303 health sciences ,lcsh:R5-920 ,Cilium ,Cell Biology ,Actin cytoskeleton ,Phenotype ,Cell biology ,lcsh:Genetics ,Vesicular trafficking ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Function (biology) - Abstract
The uncharacterized gene KIAA1109 has recently been associated with a congenital neurological malformation disorder that variably presents with arthrogryposis, craniofacial and/or cardiac abnormalities. We have identified two additional patients with compound heterozygous KIAA1109 variants presenting with the same neurological malformations. The mechanism whereby KIAA1109 loss of function causes this spectrum of disorders was the primary focus of our studies. We hypothesized that KIAA1109 function could be conserved relative to the fly gene tweek and examined endocytosis and endosome recycling in patient fibroblasts. Furthermore, we examined the structure of the cytoskeleton and cilia based on functional overlap with endocytosis and several known etiologies for neuronal migration disorders. Utilizing primary dermal fibroblasts from one patient and a healthy donor, we performed immunofluorescence and endocytosis assays to examine the endosomal, cytoskeletal, and ciliary cellular phenotypes. We found notable abnormalities in endosomal trafficking and endosome recycling pathways. We also observed changes in the actin cytoskeleton and cilia structural dynamics. We conclude that the function of KIAA1109 in humans may indeed overlap with the function of the Drosophila ortholog, resulting in perturbations to endosomal trafficking and the actin cytoskeleton. These alterations have ripple effects, altering many pathways that are critical for proper neuronal migration and embryonic development. Keywords: Cilia, Endocytosis, KIAA1109, Neurological malformation, Vesicular trafficking
- Published
- 2019
10. eP154: Predictive genomic medicine for thoracic aortic aneurysm and dissection
- Author
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Alexander Katz, Caralynn Wilczewski, Natalie Hauser, Palak Shah, Vera Zanker, Felicia Akinwande, George Maxwell, and Leslie Biesecker
- Subjects
Genetics (clinical) - Published
- 2022
11. SCN3A ‐related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation
- Author
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Thuy Anh Vu, Sally Ackermann, Andrew E. Fry, Seok Kyu Kang, Shelagh Joss, Katrien Stouffs, Satoko Miyatake, Katherine A. Fawcett, Ethan M. Goldberg, Elena Parrini, Natalie Hauser, Anna E. Jansen, Daniela T. Pilz, Daphna Marom, Adeline Jacquinet, Katherine L. Helbig, Yuh Fujiwara, Natalie Lippa, Orit Reish, Ingo Helbig, Bruria Ben-Zeev, Shraddha Srinivasan, Pradeep Vasudevan, Renzo Guerrini, Careni Spencer, Lieve Verstraete, Agnieszka Charzewska, Christopher H. Thompson, Jérôme Clatot, Jennifer A. Kearney, David R. FitzPatrick, Haim Bassan, Victoria Harrison, Naomichi Matsumoto, Tariq Zaman, Dorota Hoffman-Zacharska, Clinical sciences, Medical Genetics, Reproduction and Genetics, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, and Neurogenetics
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,Biology ,Sodium Channels ,Article ,03 medical and health sciences ,Epilepsy ,SCN3A ,0302 clinical medicine ,Neurodevelopmental disorder ,Fetus ,Channelopathy ,Intellectual disability ,medicine ,NAV1.3 Voltage-Gated Sodium Channel ,Missense mutation ,Humans ,Child ,Sodium channel ,Brain ,Genetic Variation ,Infant ,medicine.disease ,Electrophysiology ,030104 developmental biology ,HEK293 Cells ,Neurology ,Neurodevelopmental Disorders ,Child, Preschool ,Female ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Objective\ud \ud Pathogenic variants in SCN3A , encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood‐onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A ‐related neurodevelopmental disorder.\ud Methods\ud \ud Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type vs. variant Nav1.3 subunits co‐expressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293 T cells).\ud Results\ud \ud Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4–6 of domains II‐IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.\ud Interpretation\ud \ud Our study defines SCN3A‐ related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis.
- Published
- 2020
12. Mosaicism in ASXL3-related syndrome: Description of five patients from three families
- Author
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Katrina Prescott, Anna Platt, Sumit Punj, Meena Balasubramanian, Deciphering Developmental Disorders Study, Schaida Schirwani, Sahar Mansour, Natalie Hauser, and Natalie Canham
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0301 basic medicine ,Male ,Developmental Disabilities ,Germline mosaicism ,Disease ,030105 genetics & heredity ,Saliva sample ,Biology ,Germline ,03 medical and health sciences ,Neurodevelopmental disorder ,Genetics ,medicine ,Humans ,Child ,Gene ,Genetics (clinical) ,Mechanism (biology) ,Mosaicism ,General Medicine ,medicine.disease ,Pedigree ,genomic DNA ,030104 developmental biology ,Child, Preschool ,Mutation ,Female ,Transcription Factors - Abstract
De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome.
- Published
- 2020
13. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants
- Author
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Jennifer Tarpinian, Alberto Fernández-Jaén, Deborah A. Nickerson, Michael J. Bamshad, Kosuke Izumi, Giovanni Battista Ferrero, Emma Bedoukian, Marcello Niceta, Brendan Lee, A. Micheil Innes, Yuri A. Zarate, Katherine A. Bosanko, Annie Laquerrière, Jennifer A. Bassetti, David Mowat, Beth Keena, Carolina Galaz-Montoya, Claudia Gonzaga-Jauregui, Boris Keren, Reid Sutton, Elaine H. Zackai, James R. Lupski, Constance F. Wells, Francesca Clementina Radio, Natalie Hauser, Dong Li, Grace U Ediae, Marco Tartaglia, Xiang-Jiao Yang, Para Chottil Soumya, Elizabeth J. Bhoj, Christine Coubes, Kinattinkara R. Subbaraman, Alain Verloes, Klaus Dieterich, John C. Carey, Mary K. Kukolich, Francisco Cammarata-Scalisi, Alper Gezdirici, Jessica X. Chong, Sirinart Molidperee, Amelle Shillington, Sarah L. Sawyer, David S. Liu, Ana Bracho, Li Xin Zhang, Richard A. Gibbs, Sheela Nampoothiri, Ingrid A. Holm, Philip M. Boone, Alyssa Ritter, Charlotte Dubucs, Philippe M. Campeau, Gabrielle Lemire, Maria Lisa Dentici, Jacqueline Aziza, Frank J. Probst, Karippoth Mohandas Nair, Millan S. Patel, and Chester W. Brown
- Subjects
0301 basic medicine ,Say–Barber–Biesecker–Young–Simpson syndrome ,030105 genetics & heredity ,Blepharophimosis ,Bioinformatics ,KAT6B ,Article ,03 medical and health sciences ,genitopatellar syndrome ,KAT6B disorders ,SBBYSS ,Intellectual Disability ,Genotype ,Medicine ,Humans ,Allele ,Increased nuchal translucency ,Genetics (clinical) ,Histone Acetyltransferases ,Optic nerve hypoplasia ,Polydactyly ,business.industry ,Enfermedades genéticas congénitas ,Pediatría ,Embriología ,Cystic hygroma ,Exons ,medicine.disease ,Genética ,030104 developmental biology ,Intestinal malrotation ,Mutation ,Genitopatellar syndrome ,business - Abstract
Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM
- Published
- 2020
14. Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital
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Rajiv Baveja, Benjamin D. Solomon, Thierry Vilboux, Natalie Hauser, Dale L. Bodian, and Alina Khromykh
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0301 basic medicine ,Adult ,Heart Defects, Congenital ,Male ,Hospitals, Community ,030105 genetics & heredity ,Bioinformatics ,03 medical and health sciences ,Genetics ,Medicine ,Humans ,Child ,Molecular Biology ,Genetics (clinical) ,Whole genome sequencing ,whole genome sequencing ,Base Sequence ,business.industry ,Genomic sequencing ,Infant, Newborn ,Infant ,Original Articles ,Genomics ,Sequence Analysis, DNA ,congenital heart disease ,Community hospital ,030104 developmental biology ,Child, Preschool ,Cardiac defects ,Original Article ,Female ,genetic ,business - Abstract
Background Congenital cardiac defects, whether isolated or as part of a larger syndrome, are the most common type of human birth defect occurring on average in about 1% of live births depending on the malformation. As there is an expanding understanding of the underlying molecular mechanisms by which a cardiac defect may occur, there is a need to assess the current rates of diagnosis of cardiac defects by molecular sequencing in a clinical setting. Methods and Results In this report, we evaluated 34 neonatal and pediatric patients born with a cardiac defect and their parents using exomized preexisting whole genome sequencing (WGS) data to model clinically available exon‐based tests. Overall, we identified candidate variants in previously reported cardiac‐related genes in 35% (12/34) of the probands. These include clearly pathogenic variants in two of 34 patients (6%) and variants of uncertain significance in relevant genes in 10 patients (26%), of these latter 10, 2 segregated with clinically apparent findings in the family trios. Conclusions These findings suggest that with current knowledge of the proteins underlying CHD, genomic sequencing can identify the underlying genetic etiology in certain patients; however, this technology currently does not have a high enough yield to be of routine clinical use in the screening of pediatric congenital cardiac defects.
- Published
- 2018
15. Novel variant in TGM6 gene in patient with spinocerebellar ataxia 35 exhibiting a rapid onset and progression of movement disorder
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Julia Pascal, Natalie Hauser, and Jessica Merberg
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,Biochemistry ,Endocrinology ,Rapid onset ,Genetics ,Spinocerebellar ataxia ,Medicine ,In patient ,business ,Molecular Biology ,Neuroscience ,Gene - Published
- 2021
16. Baraitser-Winter syndrome in a male patient with a uterus
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Carolina Saldarriaga Perez, Callie Diamonstein, and Natalie Hauser
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Pediatrics, Perinatology and Child Health - Published
- 2020
17. EPG5 Variants with Modest Functional Impact Result in an Ameliorated and Primarily Neurological Phenotype in a 3.5-Year-Old Patient with Vici Syndrome
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Amelia Diplock, Wendy E. Smith, John E. Niederhuber, Jia Zhao, Thierry Vilboux, John F. Deeken, Natalie Hauser, Megan S. Kane, Darius Ebrahimi-Fakhari, Julie Muskett, and Siddharth Srivastava
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Vesicular Transport Proteins ,Autophagy-Related Proteins ,030105 genetics & heredity ,Compound heterozygosity ,Severity of Illness Index ,Cataract ,Corpus Callosum ,03 medical and health sciences ,0302 clinical medicine ,Cataracts ,medicine ,Humans ,Vici syndrome ,Global developmental delay ,Agenesis of the corpus callosum ,Hypopigmentation ,business.industry ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Hypotonia ,Phenotype ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,Neurology (clinical) ,medicine.symptom ,Agenesis of Corpus Callosum ,business ,030217 neurology & neurosurgery ,Congenital disorder - Abstract
Congenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 (EPG5)-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of EPG5 variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous EPG5 variants [NM_020964.2: c.772G > T/c.5943–9_5943–5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the EPG5 variants present would be milder with a higher amount of residual EPG5 expression. Analyses of EPG5 messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing; mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of EPG5 expression.
- Published
- 2019
18. Novel GABRA2 variants in epileptic encephalopathy and intellectual disability with seizures
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Kirsty McWalter, Ann M. Bergin, Laurence Hubert, Natalie Hauser, Ian C. Forster, Cécile Freihuber, Boris Keren, Julien Buratti, Lance H. Rodan, Ye Htet Aung, Christel Depienne, Rebecca Miller, Karine Poirier, Aurélie Lafitte, Caroline Nava, Cyril Mignot, Snezana Maljevic, Arnold Munnich, Eric LeGuern, Claude Besmond, Steven Petrou, Rima Nabbout, and Delphine Héron
- Subjects
Epilepsy ,biology ,business.industry ,Epileptic encephalopathy ,Medizin ,Receptors, GABA-A ,medicine.disease ,Bioinformatics ,Clinical neurology ,Seizures ,Intellectual Disability ,Intellectual disability ,biology.protein ,medicine ,Humans ,Epilepsy, Generalized ,GABRA2 ,Neurology (clinical) ,business ,De novo mutations - Published
- 2019
19. A case study of atypical Larsen syndrome with absent hallmark joint dislocations
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Callie Diamonstein, Neslida Kodra, and Natalie Hauser
- Subjects
0301 basic medicine ,Proband ,Adult ,Male ,Filamins ,Joint Dislocations ,030105 genetics & heredity ,Biology ,skeletal dysplasia ,Osteochondrodysplasias ,Clinical Reports ,03 medical and health sciences ,symbols.namesake ,Genetics ,medicine ,Coding region ,Humans ,FLNB ,Larsen syndrome ,Joint dislocation ,Craniofacial ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,Sanger sequencing ,Clinical Report ,Infant, Newborn ,Infant ,medicine.disease ,Pedigree ,030104 developmental biology ,Phenotype ,symbols ,Female ,phenotypic variability ,whole‐exome sequencing - Abstract
Background A family with skeletal and craniofacial anomalies is presented. Whole‐exome sequencing (WES) analysis indicated a diagnosis of Larsen syndrome, although their clinical presentation does not include the hallmark joint dislocations typically observed in Larsen syndrome. Methods Patient consent for the sharing of de‐identified clinical and genetic information, along with use of photographs for publication, was obtained. WES and variant segregation analysis by WES were performed by commercial laboratory, GeneDx (Gaithersburg, MD), on peripheral blood samples from the proband, her brother, and her parents using methods detailed on their website for test XomeDx Whole Exome Sequencing Trio (https://www.genedx.com/test-catalog/available-tests/xomedx-whole-exome-sequencing-trio/). WES uses next‐generation sequencing (NGS) technology to assess for variants within the coding regions, or exons, of approximately 23,000 genes. For the FLNB gene (NM_001457.3), 100% of the coding region was covered at a minimum of 10x. GeneDx uses Sanger sequencing to confirm NGS variants. Results WES revealed a heterozygous pathogenic variant, p.Glu227Lys (c.679G>A), in the FLNB gene in three out of the four family members tested. This variant is associated with Larsen syndrome, a skeletal dysplasia condition with a wide range of phenotypic variability that usually includes congenital joint dislocations. Conclusion This is a highly unusual presentation of Larsen syndrome in which the identifying hallmark trait is absent in the patients’ phenotypes.
- Published
- 2018
20. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome
- Author
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Ssang-Taek Lim, Helger G. Yntema, Tara Funari, Alexander P.A. Stegmann, Daniel G. MacArthur, Jung-Hyun Kim, Bert B.A. de Vries, Alyson Krokosky, Joost Nicolai, Sha Tang, Serge Romana, Megan T. Cho, Joris A. Veltman, Berivan Baskin, Vandana Shashi, Clesson Turner, Deepali N. Shinde, Maja Hempel, Franco Laccone, Lisenka E.L.M. Vissers, Richard M. Myers, Grazia M.S. Mancini, Daniëlle G.M. Bosch, Eun-Young Erin Ahn, Tamison Jewett, Ganka Douglas, Margot R.F. Reijnders, Eun Young Park, Axel Neu, Dong-Er Zhang, Joshua K. Stone, Davor Lessel, Connie T.R.M. Stumpel, Helga Rehder, Christopher T. Gordon, Luis Rohena, Laurie B. Owen, Dima El-Khechen, Jana Behunova, Tim M. Strom, Julie Vogt, Andrea H. Seeley, Kirsty McWalter, Nuria C. Bramswig, Margje Sinnema, Marlène Rio, Natalie Hauser, Rebecca L. Belmonte, Servi J. C. Stevens, Kristin Lindstrom, Han G. Brunner, Fanny Kortüm, Kelly Schoch, Amber Begtrup, Kristine K. Bachman, Paula A. Bubulya, Stephanie L. Santoro, Jos M. T. Draaisma, Dagmar Wieczorek, Xu Yao, David L. Stachura, Slavé Petrovski, Gregory R. Wilson, David Traver, Clinical Genetics, Genetica & Celbiologie, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), and MUMC+: DA Klinische Genetica (5)
- Subjects
0301 basic medicine ,Male ,Developmental Disabilities ,Medizin ,Haploinsufficiency ,Bioinformatics ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,0302 clinical medicine ,Intellectual disability ,FLNA ,Genetics(clinical) ,Eye Abnormalities ,Zebrafish ,Genetics (clinical) ,Genetics ,Gene knockdown ,Genes, Essential ,biology ,Brain ,Syndrome ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Pedigree ,DNA-Binding Proteins ,RNA splicing ,Female ,Heterozygote ,RNA Splicing ,Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] ,Minor Histocompatibility Antigens ,03 medical and health sciences ,Metabolic Diseases ,Intellectual Disability ,Report ,medicine ,Animals ,Humans ,RNA, Messenger ,Gene ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,RNA ,medicine.disease ,biology.organism_classification ,Spine ,030104 developmental biology ,Mutation ,Head ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 167701.pdf (Publisher’s version ) (Open Access) The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
- Published
- 2016
21. Diagnosis of LCHAD/TFP deficiency in an at risk newborn using umbilical cord blood acylcarnitine analysis
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Brendan C. Lanpher, Debra S. Regier, Kristina Cusmano-Ozog, Omar B. Ayyub, Natalie Hauser, Laura H. Kofman, Callie Jenevein, and Donna B. Raval
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0301 basic medicine ,medicine.medical_specialty ,Cardiomyopathy ,Case Report ,Umbilical cord ,03 medical and health sciences ,Umbilical cord blood ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Ketogenesis ,Genetics ,medicine ,LCHAD ,Decompensation ,lcsh:QH301-705.5 ,Molecular Biology ,Beta oxidation ,Free carnitine ,lcsh:R5-920 ,business.industry ,medicine.disease ,Surgery ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Inborn error of metabolism ,Lactic acidosis ,Long-chain hydroxyacyl-CoA dehydrogenase deficiency ,lcsh:Medicine (General) ,business ,030217 neurology & neurosurgery - Abstract
Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency.
- Published
- 2016
22. Rapidly growing, multifocal, benign choroid plexus tumor in an infant: case report
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Kalina A. Misiolek, Natalie Hauser, Zachary G. Osborn, Daniel H. Fulkerson, Diana L. Thomas, and Jessica Goodman
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Pathology ,medicine.medical_specialty ,Third ventricle ,business.industry ,General Medicine ,medicine.disease ,Aicardi syndrome ,Hydrocephalus ,03 medical and health sciences ,Lateral ventricles ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Papilloma ,Choroid plexus ,Choroid plexus tumor ,business ,Agenesis of the corpus callosum ,030217 neurology & neurosurgery - Abstract
Choroid plexus papillomas (CPPs) are rare, benign tumors that can arise in young children. Most pediatric patients present with signs of hydrocephalus and require immediate treatment. The natural history of choroid plexus tumors in children without hydrocephalus is poorly defined. In this report, the authors present the very rare case of a child without hydrocephalus but with two intraventricular choroid plexus tumors discovered shortly after birth. Initial imaging had been performed for seizures and showed agenesis of the corpus callosum and enhancing tumors in the third and left lateral ventricles. Sequential imaging demonstrated rapid growth of both tumors. The lateral tumor was removed when the child was 3 months of age. A histological examination of the specimen showed benign features with an elevated mitotic rate. Given the patient’s age of under 3 years, the diagnosis was WHO grade I CPP. The third ventricle tumor grew rapidly. A second surgery was performed and this tumor was resected. Again, the pathological diagnosis was WHO grade I CPP. The authors present this rare case and discuss the current relevant literature.
- Published
- 2018
23. Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1
- Author
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Benjamin Bender, Alleene V. Strickland, Michael A. Gonzalez, Marina L. Kennerson, Hans Offenbacher, Rebecca Schüle, Michaela Auer-Grumbach, Stephan Züchner, Reinhard Windhager, Michaela Brunner-Krainz, Avencia Sanchez Mejias Garcia, Peter Young, Natalie Hauser, Maria Schabhüttl, Matthew B. Harms, Michael E. Shy, Steven A. Moore, Stephan Klebe, Ursula Gruber-Sedlmayr, and Matthis Synofzik
- Subjects
Cytoplasmic Dyneins ,DYNC1H1 protein, human ,pathology [Motor Neuron Disease] ,pathology [Motor Neurons] ,DNA Mutational Analysis ,Dynein ,genetics [Cytoplasmic Dyneins] ,Biology ,Article ,pathology [Muscle, Skeletal] ,Charcot-Marie-Tooth Disease ,Microtubule ,pathology [Charcot-Marie-Tooth Disease] ,Cytoplasmic dynein complex ,medicine ,Humans ,ddc:610 ,Motor Neuron Disease ,Muscle, Skeletal ,Gene ,Exome sequencing ,Dominance (genetics) ,Motor Neurons ,Genetics ,Spinal muscular atrophy ,medicine.disease ,Phenotype ,Neurology ,Mutation ,genetics [Motor Neuron Disease] ,Neurology (clinical) ,genetics [Charcot-Marie-Tooth Disease] - Abstract
Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development (MCD), and Charcot-Marie-Tooth disease, type 2O (CMT2O). We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore we analysed our database of 1,024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
- Published
- 2015
24. Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA)
- Author
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Irini Manoli, Jennifer L. Sloan, Natalie Hauser, Yiouli P. Ktena, Charles P. Venditti, Andrea L. Gropman, and Scott M. Paul
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medicine.medical_specialty ,Movement disorders ,Rehabilitation ,Referral ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Methylmalonic acidemia ,Chorea ,Neurological examination ,medicine.disease ,Quality of life ,Genetics ,medicine ,Physical therapy ,medicine.symptom ,business ,Genetics (clinical) ,Natural history study - Abstract
Methylmalonic acidemia patients have complex rehabilitation needs that can be targeted to optimize societal independence and quality of life. Thirty-seven individuals with isolated MMA (28 mut, 5 cblA, 4 cblB), aged 2–33 years, were enrolled in a natural history study, and underwent age-appropriate clinical assessments to characterize impairments and disabilities. Neurological examination and brain imaging studies were used to document movement disorders and the presence of basal ganglia injury. A range of impairments and disabilities were identified by a team of physical medicine experts. Movement disorders, such as chorea and tremor, were common (n = 31, 83%), even among patients without evidence of basal ganglia injury. Joint hypermobility (n = 24, 69%) and pes planus (n = 22, 60%) were frequent and, in many cases, under-recognized. 23 (62%) patients required gastrostomy feedings. 18/31 patients >4 years old (58%) had difficulties with bathing and dressing. 16 of 23 school-aged patients received various forms of educational support. Five of the 10 adult patients were employed or in college; three lived independently. Unmet needs were identified in access to rehabilitation services, such as physical therapy (unavailable to 14/31), and orthotics (unavailable to 15/22). We conclude that patients with MMA are challenged by a number of functional limitations in essential activities of mobility, self-care, and learning, in great part caused by movement disorders and ligamentous laxity. Early assessment, referral, and implementation of age-appropriate rehabilitation services should significantly improve independence and quality of life. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
25. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations
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Felix Distelmaier, Vassiliki Konstantopoulou, Anna Schossig, Jozef Hertecant, Darius Ebrahimi-Fakhari, Karen Leydiker, Brett H. Graham, Nicole I. Wolf, Daniela Karall, Johannes A. Mayr, Saskia B. Wortmann, Natalie Hauser, Sabine Scholl-Bürgi, Tobias B. Haack, Wolfgang Sperl, Fatma Al Jasmi, Ekkehard Wilichowski, Holger Prokisch, Charles Marques Lourenço, Penelope E. Bonnen, Martina Huemer, Caroline Biagosch, Peter Freisinger, Robert W. Taylor, Robert McFarland, Jose E. Abdenur, Pediatric surgery, and NCA - Brain mechanisms in health and disease
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Mitochondrial Diseases ,Mitochondrial disease ,Ubiquitin-Protein Ligases ,Encephalopathy ,Respiratory chain ,Physiology ,Neuroimaging ,Article ,Atrophy ,Genetics ,Medicine ,Humans ,Family ,Child ,Genetics (clinical) ,Genetic Association Studies ,Retrospective Studies ,Muscular hypotonia ,business.industry ,F-Box Proteins ,Infant, Newborn ,Infant ,Metabolic acidosis ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,medicine.disease ,Prognosis ,Facial Asymmetry ,Child, Preschool ,Failure to thrive ,Mutation ,Disease Progression ,Muscle Hypotonia ,Acidosis, Lactic ,Female ,medicine.symptom ,business ,Severe lactic acidosis - Abstract
Contains fulltext : 154784.pdf (Publisher’s version ) (Closed access) FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.
- Published
- 2015
26. Severe bilateral cerebellar edema from ingestion of ketamine: case report
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Thomas Gianaris, Natalie Hauser, Blake A. Froberg, Nicolas W. Villelli, and Daniel H. Fulkerson
- Subjects
Context (language use) ,Brain Edema ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,Edema ,Intervention (counseling) ,Cerebellum ,Cerebellar edema ,medicine ,Ingestion ,Humans ,Ketamine ,Analgesics ,business.industry ,Clinical course ,Infant ,General Medicine ,Magnetic Resonance Imaging ,Anesthesia ,Accidental ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The use of ketamine as a drug of abuse has increased and so too has the risk of accidental overdose. Here, the authors report the case of a 10-month-old infant who inadvertently ingested ketamine. The child demonstrated severe cerebellar swelling that required emergency surgical intervention. The authors describe the clinical course of this child and present the radiographic characteristics of the brain. The imaging characteristics were not consistent with purely anoxic injury, thus suggesting a specific effect of this drug. To the authors’ knowledge, similar imaging characteristics in this context have not been described.
- Published
- 2017
27. Genomic analysis of an infant with intractable diarrhea and dilated cardiomyopathy
- Author
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Callie Jenevein, Benjamin D. Solomon, Dale L. Bodian, Alina Khromykh, Kathleen C. Kent, Suchitra K. Hourigan, Thierry Vilboux, Haresh Mani, and Natalie Hauser
- Subjects
0301 basic medicine ,Proband ,Research Report ,Cardiomyopathy, Dilated ,Diarrhea ,medicine.medical_specialty ,Cousin ,intractable diarrhea ,030204 cardiovascular system & hematology ,Bioinformatics ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Malabsorption Syndromes ,Internal medicine ,medicine ,Humans ,Intestinal Mucosa ,Genetic testing ,medicine.diagnostic_test ,Whole Genome Sequencing ,business.industry ,Infant, Newborn ,Infant ,Dilated cardiomyopathy ,Sequela ,General Medicine ,Genomics ,medicine.disease ,Epithelial Cell Adhesion Molecule ,Phenotype ,Congenital tufting enteropathy ,Introns ,dilated cardiomyopathy ,Intestines ,030104 developmental biology ,Diarrhea, Infantile ,Mutation ,Cardiology ,Female ,Differential diagnosis ,business - Abstract
We describe a case of an infant presenting with intractable diarrhea who subsequently developed dilated cardiomyopathy, for whom a diagnosis was not initially achieved despite extensive clinical testing, including panel-based genetic testing. Research-based whole-genome sequences of the proband and both parents were analyzed by the SAVANNA pipeline, a variant prioritization strategy integrating features of variants, genes, and phenotypes, which was implemented using publicly available tools. Although the intestinal morphological abnormalities characteristic of congenital tufting enteropathy (CTE) were not observed in the initial clinical gastrointestinal tract biopsies of the proband, an intronic variant, EPCAM c.556-14A>G, previously identified as pathogenic for CTE, was found in the homozygous state. A newborn cousin of the proband also presenting with intractable diarrhea was found to carry the same homozygous EPCAM variant, and clinical testing revealed intestinal tufting and loss of EPCAM staining. This variant, however, was considered nonexplanatory for the proband's dilated cardiomyopathy, which could be a sequela of the child's condition and/or related to other genetic variants, which include de novo mutations in the genes NEDD4L and GSK3A and a maternally inherited SCN5A variant. This study illustrates three ways in which genomic sequencing can aid in the diagnosis of clinically challenging patients: differential diagnosis despite atypical clinical presentation, distinguishing the possibilities of a syndromic condition versus multiple conditions, and generating hypotheses for novel contributory genes.
- Published
- 2017
28. MRI Characteristics of Globus Pallidus Infarcts in Isolated Methylmalonic Acidemia
- Author
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Irini Manoli, Camilo Toro, Eva H. Baker, Andrea L. Gropman, Jennifer L. Sloan, David R. Adams, Charles P. Venditti, and Natalie Hauser
- Subjects
Brain Infarction ,Male ,endocrine system ,Pathology ,medicine.medical_specialty ,Methylmalonic acidemia ,Substantia nigra ,Globus Pallidus ,Pediatrics ,Cohort Studies ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,Amino Acid Metabolism, Inborn Errors ,medicine.diagnostic_test ,business.industry ,musculoskeletal, neural, and ocular physiology ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,nervous system diseases ,Isolated Methylmalonic Acidemia ,Globus pallidus ,nervous system ,Inborn error of metabolism ,Anesthesia ,Female ,Neurology (clinical) ,CBLB ,Pars reticulata ,business - Abstract
BACKGROUND: Bilateral infarcts confined to the globus pallidus are unusual and occur in conjunction with only a few disorders, including isolated methylmalonic acidemia, a heterogeneous inborn error of metabolism. On the basis of neuroradiographic features of metabolic strokes observed in a large cohort of patients with methylmalonic acidemia, we have devised a staging system for methylmalonic acidemia–related globus pallidus infarcts. MATERIALS AND METHODS: Forty patients with isolated methylmalonic acidemia and neurologic symptoms underwent clinical brain MR imaging studies, which included 3D-T1WI. Infarcted globus pallidus segments were neuroanatomically characterized, and infarct volumes were measured. RESULTS: Globus pallidus infarcts were present in 19 patients; all were bilateral, and most were left-dominant. A neuroanatomic scoring system based on the infarct patterns was devised; this revealed a 5-stage hierarchical susceptibility to metabolic infarct, with the posterior portion of the globus pallidus externa being the most vulnerable. Globus pallidus infarct prevalence by methylmalonic acidemia class was the following: cblA (5/7, 71%), cblB (3/7, 43%), mut o (10/22, 45%), and mut- (1/4, 25%). Tiny lacunar infarcts in the pars reticulata of the substantia nigra, previously unrecognized in methylmalonic acidemia, were found in 17 patients, 13 of whom also had a globus pallidus infarct. CONCLUSIONS: The staged pattern of globus pallidus infarcts in isolated methylmalonic acidemia suggests a nonuniform, regionally specific cellular susceptibility to metabolic injury, even for patients having milder biochemical phenotypes. In support of this hypothesis, the delineation of lacunar infarcts in the pars reticulata of the substantia nigra, a tissue functionally and histologically identical to the globus pallidus interna, supports the concept of cell-specific pathology.
- Published
- 2014
29. FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants
- Author
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Birgit Zirn, Wolfram Heinritz, Keri Ramsey, Milka Pringsheim, Angelika Rieß, Dörthe Malzahn, Marc Kaulisch, Hans Martin Büttel, Katherine L. Helbig, Johannes R. Lemke, Luis Rohena, Martina Baethmann, G. Christoph Korenke, Frank Martin Zech, Marion Heruth, Isabelle Prehl, Konstanze Hoertnagel, Kim Sarah Plümacher, Knut Brockmann, Carolina Courage, Gerhard Kluger, Stephanie Karch, Karen Höft, Diana Mitter, Barbara Zoll, Julie S. Cohen, Angelika Eger, Rami Abou Jamra, Steffi Patzer, Theresa A. Grebe, Simone Schröder, Ali Fatemi, Dagmar Huhle, Richard E. Lutz, Tina Rating, Elizabeth Conover, Mareike Schimmel, Thomas Bast, Rita Warthemann, Rachel Westman, and Natalie Hauser
- Subjects
0301 basic medicine ,Male ,Genotype ,Genetic counseling ,Protein domain ,DNA Mutational Analysis ,Nerve Tissue Proteins ,Biology ,Polymorphism, Single Nucleotide ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,Forkhead Transcription Factors ,Genetic variation ,Rett Syndrome ,Missense mutation ,Humans ,Child ,Genetics (clinical) ,Genetic Association Studies ,Genetics ,Genetic Variation ,Magnetic Resonance Imaging ,3. Good health ,FOXG1 ,030104 developmental biology ,Phenotype ,Child, Preschool ,Female ,030217 neurology & neurosurgery - Abstract
PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.
- Published
- 2016
30. Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn
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Megan S. Kane, Ashleigh R. Pavey, John E. Niederhuber, Dale L. Bodian, Elisabeth Klein, Benjamin D. Solomon, Alina Khromykh, Thierry Vilboux, Aaron Black, Kathi Huddleston, Ramaswamy K. Iyer, and Natalie Hauser
- Subjects
0301 basic medicine ,Male ,Genotype ,030105 genetics & heredity ,Genome ,03 medical and health sciences ,Neonatal Screening ,Medicine ,Humans ,Genetic Testing ,Gene ,Genetics (clinical) ,Immunodeficiency ,Data Curation ,Whole genome sequencing ,Genetics ,Newborn screening ,Whole Genome Sequencing ,business.industry ,Complement component 9 ,Genomic sequencing ,Immunologic Deficiency Syndromes ,Infant, Newborn ,Computational Biology ,medicine.disease ,030104 developmental biology ,Phenotype ,Cohort ,Female ,business - Abstract
PurposeImmunodeficiency screening has been added to many state-directed newborn screening programs. The current methodology is limited to screening for severe T-cell lymphopenia disorders. We evaluated the potential of genomic sequencing to augment current newborn screening for immunodeficiency, including identification of non-T cell disorders.MethodsWe analyzed whole-genome sequencing (WGS) and clinical data from a cohort of 1,349 newborn-parent trios by genotype-first and phenotype-first approaches. For the genotype-first approach, we analyzed predicted protein-impacting variants in 329 immunodeficiency-related genes in the WGS data. As a phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodeficiency. Genomes of these children and their parents were analyzed using a separate pipeline for identification of candidate pathogenic variants for rare Mendelian disorders.ResultsWGS provides adequate coverage for most known immunodeficiency-related genes. 13,476 distinct variants and 8,502 distinct predicted protein-impacting variants were identified in this cohort; five individuals carried potentially pathogenic variants requiring expert clinical correlation. One clinically asymptomatic individual was found genomically to have complement component 9 deficiency. Of the symptomatic children, one was molecularly identified as having an immunodeficiency condition and two were found to have other molecular diagnoses.ConclusionNeonatal genomic sequencing can potentially augment newborn screening for immunodeficiency.
- Published
- 2016
31. De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism
- Author
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Jason Carmichael, Jeffrey W. Innis, Donald S. Petrey, Linshan Shang, Katrina Haude, Jane L. Schuette, Megan T. Cho, Lindsay B. Henderson, Wendy K. Chung, Kyle Retterer, Margaret Pearson, Chin-To Fong, Leandra Folk, Julie Lundberg, Shailesh Asaikar, Kristin G. Monaghan, Natasha Shur, Yvonne W. Wu, and Natalie Hauser
- Subjects
0301 basic medicine ,Male ,Autism Spectrum Disorder ,Autism ,DNA Mutational Analysis ,Intellectual disabilities ,Missense mutation ,2.1 Biological and endogenous factors ,Protein Phosphatase 2 ,Aetiology ,Child ,Genetics (clinical) ,Genetics ,Pediatric ,Single Nucleotide ,Hypotonia ,PPP2R5D ,Mental Health ,Protein phosphatase ,Child, Preschool ,Whole-exome sequencing ,Muscle Hypotonia ,Female ,Cognitive Sciences ,medicine.symptom ,Adolescent ,Protein subunit ,Intellectual and Developmental Disabilities (IDD) ,1.1 Normal biological development and functioning ,Phosphatase ,Mutation, Missense ,Biology ,Polymorphism, Single Nucleotide ,Article ,Chromatin remodeling ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Underpinning research ,Intellectual Disability ,medicine ,Humans ,Genetic Predisposition to Disease ,Autistic Disorder ,Polymorphism ,Preschool ,Protein kinase B ,GSK3B ,Genetic Association Studies ,De novo mutations ,Neurology & Neurosurgery ,Neurosciences ,Infant ,Protein phosphatase 2 ,Megalencephaly ,Brain Disorders ,030104 developmental biology ,Mutation ,Missense - Abstract
Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.
- Published
- 2016
32. Deletion of GPIHBP1 causing severe chylomicronemia
- Author
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André Bensadoun, Jonathan C. Cohen, Juan Jasso, Jonathan J. Rios, Natalie Hauser, Savitha Shastry, Abhimanyu Garg, and Helen H. Hobbs
- Subjects
Proband ,Adult ,Male ,medicine.medical_specialty ,Apolipoprotein B ,Apolipoprotein C-II ,Gene Dosage ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Cytogenetics ,0302 clinical medicine ,Internal medicine ,Chylomicrons ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Child ,Genetics (clinical) ,030304 developmental biology ,Receptors, Lipoprotein ,Hypertriglyceridemia ,0303 health sciences ,Lipoprotein lipase ,biology ,Heparin ,Homozygote ,GPIHBP1 ,Infant ,Middle Aged ,medicine.disease ,3. Good health ,Lipoprotein Lipase ,Endocrinology ,Child, Preschool ,Mutation ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Original Article ,Female ,Carrier Proteins ,Gene Deletion ,Chylomicron ,Lipoprotein - Abstract
Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1. Electronic supplementary material The online version of this article (doi:10.1007/s10545-011-9406-5) contains supplementary material, which is available to authorized users.
- Published
- 2011
33. Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations
- Author
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Jennifer Graf, Charles P. Venditti, Irini Manoli, Jennifer L. Sloan, and Natalie Hauser
- Subjects
Adult ,Male ,Medical food ,medicine.medical_specialty ,Adolescent ,Diet therapy ,Population ,Nutritional Status, Dietary Intake, and Body Composition ,Methylmalonic acidemia ,Medicine (miscellaneous) ,Renal function ,Biology ,Body Mass Index ,Overnutrition ,Internal medicine ,medicine ,Humans ,Resting energy expenditure ,Child ,education ,Amino Acid Metabolism, Inborn Errors ,education.field_of_study ,Nutrition and Dietetics ,Dietary management ,food and beverages ,medicine.disease ,Endocrinology ,Child, Preschool ,Body Composition ,Linear Models ,Female ,Dietary Proteins ,Energy Metabolism - Abstract
Background: Isolated methylmalonic acidemia (MMA) is managed by dietary protein restriction and medical food supplementation. Resting energy expenditure (REE) can be depressed in affected individuals for undefined reasons. Objective: The objective was to document the spectrum of nutritional approaches used to treat patients with MMA, measure REE, and analyze the dependence of REE on body composition, biochemical, and nutritional variables. Design: Twenty-nine patients with isolated MMA (22 mut, 5 cblA, 2 cblB; 15 males, 14 females; age range: 2–35 y) underwent evaluation. REE was measured with open-circuit calorimetry and compared with predicted values by using age-appropriate equations. Results: Nutritional regimens were as follows: protein restriction with medical food (n = 17 of 29), protein restriction with medical food and supplemental isoleucine or valine (n = 5 of 29), or the use of natural protein alone for dietary needs (n = 7 of 29). Most mut patients had short stature and higher percentage fat mass compared with reference controls. Measured REE decreased to 74 ± 13.6% of predicted (P 18 y (n = 7). Linear regression modeling suggested that age (P = 0.001), creatinine clearance (P = 0.01), and height z score (P = 0.04) accounted for part of the variance of measured REE per kilogram of fat-free mass (model R2 = 0.66, P < 0.0001). Conclusions: There is wide variation in the dietary treatment of MMA. Standard predictive equations overestimate REE in this population primarily due to their altered body composition and decreased renal function. Defining actual energy needs will help optimize nutrition and protect individuals from overfeeding. This trial is registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00078078","term_id":"NCT00078078"}}NCT00078078.
- Published
- 2011
34. Mutation in an alternative transcript of CDKL5 in a boy with early-onset seizures
- Author
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John M. Schreiber, Thierry Vilboux, Dale L. Bodian, Natalie Hauser, and Alina Khromykh
- Subjects
0301 basic medicine ,Proband ,Genetics ,CDKL5 ,General Medicine ,Biology ,03 medical and health sciences ,Exon ,030104 developmental biology ,0302 clinical medicine ,Mutation (genetic algorithm) ,Gene ,030217 neurology & neurosurgery ,Exome sequencing ,Intractable seizures ,Early onset - Abstract
Infantile-onset epilepsies are a set of severe, heterogeneous disorders for which clinical genetic testing yields causative mutations in ∼20%–50% of affected individuals. We report the case of a boy presenting with intractable seizures at 2 wk of age, for whom gene panel testing was unrevealing. Research-based whole-genome sequencing of the proband and four unaffected family members identified a de novo mutation, NM_001323289.1:c.2828_2829delGA in CDKL5, a gene associated with X-linked early infantile epileptic encephalopathy 2. CDKL5 has multiple alternative transcripts, and the mutation lies in an exon in the brain-expressed forms. The mutation was undetected by gene panel sequencing because of its intronic location in the CDKL5 transcript typically used to define the exons of this gene for clinical exon-based tests (NM_003159). This is the first report of a patient with a mutation in an alternative transcript of CDKL5. This finding suggests that incorporating alternative transcripts into the design and variant interpretation of exon-based tests, including gene panel and exome sequencing, could improve the diagnostic yield.
- Published
- 2018
35. TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis
- Author
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Nan Wu, Xuan Ming, Jianqiu Xiao, Zhihong Wu, Xiaoli Chen, Marwan Shinawi, Yiping Shen, Guangju Yu, Jiaqi Liu, Hua Xie, Zoran S. Gucev, Sen Liu, Nan Yang, Hussam Al-Kateb, Jun Chen, Jian Zhang, Natalie Hauser, Ting Zhang, Velibor Tasic, Pengfei Liu, Xinlin Su, Xuedong Pan, Chunyu Liu, Liwen Wang, Joseph Shen, Jianxiong Shen, Yulin Chen, Jianguo Zhang, Kwong Wai Choy, Jun Wang, Qiqi Wang, Shugang Li, Weichen Zhou, Jin Guo, Yipeng Wang, Cheng Zhang, Hong Zhao, Yu An, Yu Zhao, Jiucun Wang, Zhenlei Liu, Yuzhi Zuo, Ye Tian, Xisheng Weng, V. Reid Sutton, Hongyan Wang, Yue Ming, Shashikant Kulkarni, Tao P. Zhong, Philip F. Giampietro, Sally L. Dunwoodie, Sau Wai Cheung, Xue Zhang, Li Jin, James R. Lupski, Guixing Qiu, and Feng Zhang
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,DNA Copy Number Variations ,Genotype ,Pedigree chart ,Scoliosis ,medicine.disease_cause ,Article ,Asian People ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Child ,Sequence Deletion ,Genetics ,Mutation ,business.industry ,General Medicine ,medicine.disease ,Null allele ,Spine ,Pedigree ,Radiography ,Phenotype ,Child, Preschool ,Medical genetics ,Female ,business ,T-Box Domain Proteins ,Chromosomes, Human, Pair 16 ,Comparative genomic hybridization - Abstract
Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions.We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P3.8×10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P1.1×10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).
- Published
- 2015
36. Whole exome sequence analysis of Peters anomaly
- Author
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Patricia G. Wheeler, Karen L. David, Eric Weh, Hannah Happ, Natalie Hauser, Brad Angle, Linda M. Reis, Erin Carney, Alex V. Levin, and Elena V. Semina
- Subjects
Male ,PAX6 Transcription Factor ,Filamins ,Nonsense mutation ,Anion Transport Proteins ,DNA Mutational Analysis ,Molecular Sequence Data ,Mutation, Missense ,Lyases ,Nerve Tissue Proteins ,Biology ,Compound heterozygosity ,Antiporters ,Article ,Dysgenesis ,Corneal Opacity ,Anterior Eye Segment ,Prenatal Diagnosis ,Genetics ,Missense mutation ,FLNA ,Humans ,Paired Box Transcription Factors ,Exome ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Eye Abnormalities ,Child ,Eye Proteins ,Genetics (clinical) ,Exome sequencing ,Genetic Association Studies ,Homeodomain Proteins ,Sequence Analysis, RNA ,Infant ,Pedigree ,Repressor Proteins ,Transcription Factor AP-2 ,Mutation (genetic algorithm) - Abstract
Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the first study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.
- Published
- 2014
37. Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility
- Author
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Maria J. Matas Aguilera, Loretta W Mahon, Mary Haddadin, Trilochan Sahoo, Zhijie Jiang, Kimberly A Kopita, Leslie Ross, Morteza Hemmat, Boris T Wang, Juan Lopez Siles, Klaas J. Wierenga, Fatih Z Boyar, Charles M. Strom, Arturo Anguiano, Mohammed El Naggar, Linda M. Randolph, Jia-Chi Wang, Joseph A. Church, Joseph J. Shen, Marilyn C. Jones, Natalie Hauser, John Chase, and Renius Owen
- Subjects
Adult ,Male ,Adolescent ,Intellectual and Developmental Disabilities (IDD) ,Clinical Sciences ,Genes, Recessive ,Consanguinity ,Biology ,Identity by descent ,Polymorphism, Single Nucleotide ,Article ,Chromosome 15 ,Young Adult ,Rare Diseases ,Clinical Research ,Angelman syndrome ,medicine ,Genetics ,Recessive ,Humans ,Family ,Genetic Predisposition to Disease ,Allele ,Polymorphism ,Preschool ,Child ,Genetics (clinical) ,Genetic Association Studies ,Oligonucleotide Array Sequence Analysis ,Genetics & Heredity ,Chromosome Aberrations ,Incidence ,Human Genome ,Homozygote ,Single Nucleotide ,medicine.disease ,Inflammatory Bowel Diseases ,Uniparental disomy ,Brain Disorders ,Uniparental Isodisomy ,Genes ,Child, Preschool ,Female ,Trisomy - Abstract
Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso- and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso- and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader–Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.
- Published
- 2013
38. New frontiers in neuroimaging applications to inborn errors of metabolism
- Author
-
Andrea L. Gropman, Morgan Prust, and Natalie Hauser
- Subjects
Pathology ,medicine.medical_specialty ,Neurological injury ,Magnetic Resonance Spectroscopy ,Endocrinology, Diabetes and Metabolism ,Context (language use) ,Biochemistry ,Article ,White matter ,Endocrinology ,Neuroimaging ,Genetics ,medicine ,Humans ,Oxidative injury ,Chronic Encephalopathy ,Molecular Biology ,Modalities ,business.industry ,Cognition ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Diffusion Tensor Imaging ,Nerve Net ,business ,Neuroscience ,Metabolism, Inborn Errors - Abstract
Most inborn errors of metabolism (IEMs) are associated with potential for injury to the developing central nervous system resulting in chronic encephalopathy, though the etiopathophysiology of neurological injury have not been fully established in many disorders. Shared mechanisms can be envisioned such as oxidative injury due to over-activation of N-Methyl-d-Aspartate (NMDA) receptors with subsequent glutamatergic damage, but other causes such as energy depletion or inflammation are possible. Neuroimaging has emerged as a powerful clinical and research tool for studying the brain in a noninvasive manner. Several platforms exist to study neural networks underlying cognitive processes, white matter/myelin microstructure, and cerebral metabolism in vivo . The scope and limitations of these methods will be discussed in the context of valuable information they provide in the study and management of selected inborn errors of metabolism. This review is not meant to be an exhaustive coverage of diagnostic findings on MRI in multiple IEMs, but rather to illustrate how neuroimaging modalities beyond T1 and T2 images, can add depth to an understanding of the underlying brain changes evoked by the selected IEMs. Emphasis will be placed on techniques that are available in the clinical setting. Though technically complex, many of these modalities have moved – or soon will – to the clinical arena.
- Published
- 2011
39. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria
- Author
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Leslie G. Biesecker, Irini Manoli, Kevin O'Brien, Jennifer J. Johnston, Suma Chandrasekaran, Randy J. Chandler, Natalie Hauser, Michael D. Geschwind, Charles P. Venditti, Jennifer L. Sloan, Justin R. Sysol, William L. Nyhan, Neena L Champaigne, Heidi Dorward, Nuria Carrillo-Carrasco, Susan A. Berry, Philip M James, Bruce A. Barshop, Vassilli Valayannopoulos, Pascale de Lonlay, Julie C. Sapp, Caitlin Krause, Marjan Huizing, and Dimitar Gavrilov
- Subjects
ACSF3 ,Male ,Adolescent ,Carboxy-Lyases ,Population ,Molecular Sequence Data ,Methylmalonic acid ,Mutation, Missense ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Coenzyme A Ligases ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,education ,Exome ,Exome sequencing ,030304 developmental biology ,Aged ,0303 health sciences ,education.field_of_study ,Mutation ,Exons ,Middle Aged ,3. Good health ,Minor allele frequency ,Malonyl Coenzyme A ,chemistry ,Methylmalonic aciduria ,Child, Preschool ,Female ,030217 neurology & neurosurgery ,Metabolism, Inborn Errors ,Methylmalonic Acid - Abstract
We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in ∼1,000 control individuals, predicting a CMAMMA population incidence of ∼1:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders.
- Published
- 2011
40. Cryptic chromosomal abnormalities identified in children with congenital heart disease
- Author
-
Frederick F.B. Elder, Vidu Garg, Bill P Crider, Andrew R. Zinn, Haley A. Nichols, Lane Santos, Ashleigh A Richards, and Natalie Hauser
- Subjects
Genetics ,Chromosome Aberrations ,Heart Defects, Congenital ,Male ,education.field_of_study ,Comparative Genomic Hybridization ,medicine.diagnostic_test ,Heart disease ,Population ,Chromosomal translocation ,Biology ,Bioinformatics ,medicine.disease ,Microarray Analysis ,Pediatrics, Perinatology and Child Health ,Etiology ,medicine ,Humans ,Female ,Copy-number variation ,Abnormality ,education ,In Situ Hybridization, Fluorescence ,Genetic testing ,Comparative genomic hybridization - Abstract
Congenital heart disease (CHD) is the most common type of birth defect, and the etiology of most cases is unknown. CHD often occurs in association with other birth malformations, and only in a minority are disease-causing chromosomal abnormalities identified. We hypothesized that children with CHD and additional birth malformations have cryptic chromosomal abnormalities that might be uncovered using recently developed DNA microarray-based methodologies. We recruited 20 children with diverse forms of CHD and additional birth defects who had no chromosomal abnormality identified by conventional cytogenetic testing. Using whole-genome array comparative genomic hybridization, we screened this population, along with a matched control population with isolated heart defects, for chromosomal copy number variations. We discovered disease-causing cryptic chromosomal abnormalities in five children with CHD and additional birth defects versus none with isolated CHD. The chromosomal abnormalities included three unbalanced translocations, one interstitial duplication, and one interstitial deletion. The genetic abnormalities were predominantly identified in children with CHD and a neurologic abnormality. Our results suggest that a significant percentage of children with CHD and neurologic abnormalities harbor subtle chromosomal abnormalities. We propose that children who meet these two criteria should receive more extensive genetic testing to detect potential cryptic chromosomal abnormalities.
- Published
- 2008
41. PCR-based target sequence enrichment and next generation sequencing of 24 nuclear genes for the diagnosis of mitochondrial disorders: Yield of 262 cases
- Author
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Melanie Knight, Sumit Parikh, David Dimmock, Sharon F. Suchy, Barbara Boggs, Renkui Bai, Marni J. Falk, William J. Rhead, Sherri J. Bale, Sabrina Buchholz, Dolores Arjona, Sonia Benhamed, Craig Chinault, John G. Compton, Nizar Smaoui, Federica Gibellini, Adeline Vanderver, Mustafa Saifi, Susan Sparks, Jaimie Higgs, Yuriy Shevchenko, Jaya Ganesh, Gabriele Richard, and Natalie Hauser
- Subjects
Genetics ,Nuclear gene ,Mitochondrial disease ,Yield (chemistry) ,medicine ,Molecular Medicine ,Cell Biology ,Biology ,medicine.disease ,Molecular Biology ,DNA sequencing ,Sequence (medicine) - Published
- 2012
42. Two novel RRM2B gene mutations in a patient with autosomal recessive progressive external ophthalmoplegia, encephalopathy and cytochrome c oxidase deficiency
- Author
-
Renkui Bai and Natalie Hauser
- Subjects
biology ,business.industry ,External ophthalmoplegia ,Encephalopathy ,Cell Biology ,medicine.disease ,Molecular biology ,RRM2B Gene ,biology.protein ,Molecular Medicine ,Medicine ,Cytochrome c oxidase ,business ,Molecular Biology - Published
- 2012
43. Scoliosis and vertebral anomalies: Additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement
- Author
-
Natalie Hauser, Marwan Shinawi, Dorothy K. Grange, Geetika Khanna, Christopher D. Smyser, Joseph J. Shen, Isabel Filges, Shashikant Kulkarni, and Hussam Al-Kateb
- Subjects
Diagnostic Imaging ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Genetic counseling ,Scoliosis ,Biology ,Vertebral anomalies ,03 medical and health sciences ,Gene duplication ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,030304 developmental biology ,Oligonucleotide Array Sequence Analysis ,Chromosome Aberrations ,0303 health sciences ,Incidence (epidemiology) ,030305 genetics & heredity ,Chromosome ,Facies ,Infant ,medicine.disease ,Phenotype ,Spine ,3. Good health ,Child, Preschool ,Autism ,Female ,Chromosomes, Human, Pair 16 - Abstract
The typical chromosome 16p11.2 rearrangements are estimated to occur at a frequency of approximately 0.6 of all samples tested clinically and have been identified as a major cause of autism spectrum disorders developmental delay behavioral abnormalities and seizures. Careful examination of patients with these rearrangements revealed association with abnormal head size obesity dysmorphism and congenital abnormalities. In this report we extend this list of phenotypic abnormalities to include scoliosis and vertebral anomalies. We present detailed characterization of phenotypic and radiological data of 10 new patients nine with the 16p11.2 deletion and one with the duplication within the coordinates chr16:29366195 and 30306956 (hg19) with a minimal size of 555?kb. We discuss the phenotypical and radiological findings in our patients and review 5 previously reported patients with 16p11.2 rearrangement and similar skeletal abnormalities. Our data suggest that patients with the recurrent 16p11.2 rearrangement have increased incidence of scoliosis and vertebral anomalies. However additional studies are required to confirm this observation and to establish the incidence of these anomalies. We discuss the potential implications of our findings on the diagnosis surveillance and genetic counseling of patients with 16p11.2 rearrangement. © 2014 Wiley Periodicals Inc.
- Published
- 2014
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