172 results on '"Kym M. Boycott"'
Search Results
2. The implementation of an enhanced clinical model to improve the diagnostic yield of exome sequencing for patients with a rare genetic disease: A Canadian experience
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Grace Uwaila, Ediae, Gabrielle, Lemire, Caitlin, Chisholm, Taila, Hartley, Alison, Eaton, Matthew, Osmond, Samantha K, Rojas, Lijia, Huang, Meredith, Gillespie, Sarah L, Sawyer, and Kym M, Boycott
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Genetics ,Genetics (clinical) - Abstract
The introduction of clinical exome sequencing (ES) has provided a unique opportunity to decrease the diagnostic odyssey for patients living with a rare genetic disease (RGD). ES has been shown to provide a diagnosis in 29%-57% of patients with a suspected RGD, with as many as 70% remaining undiagnosed. There is a need to advance the clinical model of care by more formally integrating approaches that were previously considered research into an enhanced diagnostic workflow. We developed an Exome Clinic, which set out to evaluate a workflow for improving the diagnostic yield of ES for patients with an undiagnosed RGD. Here, we report the outcomes of 47 families who underwent clinical ES in the first year of the clinic. The diagnostic yield from clinical ES was 40% (19/47). Families who remained undiagnosed after ES had the opportunity for follow-up studies that included phenotyping and candidate variant segregation in relatives, genomic matchmaking, and ES reanalysis. This enhanced diagnostic workflow increased the diagnostic yield to 55% (26/47), predominantly through the resolution of variants and genes of uncertain significance. We advocate that this approach be integrated into mainstream clinical practice and highlight the importance of a coordinated translational approach for patients with RGD.
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- 2022
3. The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability
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Yan Huang, Gabrielle Lemire, Lauren C. Briere, Fang Liu, Marja W. Wessels, Xueqi Wang, Matthew Osmond, Oguz Kanca, Shenzhao Lu, Frances A. High, Melissa A. Walker, Lance H. Rodan, Michael F. Wangler, Shinya Yamamoto, Kristin D. Kernohan, David A. Sweetser, Kym M. Boycott, Hugo J. Bellen, and Clinical Genetics
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DNA, Complementary ,Microfilament Proteins ,Mutation, Missense ,Correction ,Membrane Proteins ,Nervous System Malformations ,Phenotype ,Report ,Intellectual Disability ,Microcephaly ,Genetics ,Animals ,Humans ,Drosophila ,Genetics (clinical) - Abstract
MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.
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- 2022
4. Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in <scp> PIEZO1 </scp>
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Thomas Kovesi, Samantha K. Rojas, and Kym M. Boycott
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Genetics ,Genetics (clinical) - Published
- 2023
5. The complexity of diagnosing rare disease: An organizing framework for outcomes research and health economics based on real-world evidence
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Robin Z. Hayeems, Christine Michaels-Igbokwe, Viji Venkataramanan, Taila Hartley, Meryl Acker, Meredith Gillespie, Wendy J. Ungar, Roberto Mendoza-Londona, Francois P. Bernier, Kym M. Boycott, and Deborah A. Marshall
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03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,030225 pediatrics ,Outcome Assessment, Health Care ,Exome Sequencing ,Infant, Newborn ,Humans ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
To facilitate robust economic analyses of clinical exome and genome sequencing, this study was taken up with the objective of establishing a framework for organizing diagnostic testing trajectories for patients with rare disease.We collected diagnostic investigations-related data before exome sequencing from the medical records of 228 cases. Medical geneticist experts participated in a consensus building process to develop the SOLVE Framework for organizing the complex range of observed tests. Experts categorized tests as indicator or nonindicator tests on the basis of their specificity for diagnosing rare diseases. Face validity was assessed using case vignettes.Most cases had symptom onset at birth (42.5%) or during childhood (43.4%) and had intellectual disability (73.3%). On average, the time spent seeking a diagnosis before sequencing was 1989 days (SD = 2137) and included 16 tests (SD = 14). Agreement across experts on test categories ranged from 83% to 96%. The SOLVE Framework comprised observed tests, including 186 indicator and 39 nonindicator tests across cytogenetic/molecular, biochemical, imaging, electrical, and pathology test categories.Real-world diagnostic testing data can be ascertained and organized to reflect the complexity of the journey of the patients with rare diseases. SOLVE Framework will improve the accuracy and certainty associated with value-based assessments of genomic sequencing.
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- 2022
6. Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia
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Kym M. Boycott, Lyndon Gallacher, Aziz Mhanni, Simon Sadedin, Xiaomin Dong, Kristin D. Kernohan, Arran McBride, Ismaël Alidou-D'Anjou, John Christodoulou, Zornitza Stark, Aren E Marshall, François Dragon, Samantha E Marin, Patrick Frosk, Marc R. Del Bigio, and Sophie Sleiman
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Genetics ,Dystonia ,Saccharomyces cerevisiae Proteins ,Neurodegeneration ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Saccharomyces cerevisiae ,General Medicine ,Biology ,medicine.disease ,Compound heterozygosity ,Phenotype ,Dystonic Disorders ,medicine ,Humans ,Small nucleolar RNA ,RRNA processing ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,Ribonucleoprotein - Abstract
SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.
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- 2021
7. Whole genome sequencing identifies pathogenic <scp> RNU4ATAC </scp> variants in a child with recurrent encephalitis, microcephaly, and normal stature
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Kym M. Boycott, Kristin D. Kernohan, Matt Osmond, Pranesh Chakraborty, Hugh J. McMillan, David A. Dyment, and Jorge Davila
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Microcephaly ,Spondyloepimetaphyseal dysplasia ,Pediatrics ,medicine.medical_specialty ,business.industry ,Mitochondrial disease ,Disease ,medicine.disease ,Genetics ,medicine ,Decompensation ,Primordial dwarfism ,business ,Exome ,Genetics (clinical) ,Encephalitis - Abstract
Biallelic pathogenic variants in RNU4ATAC have been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Although children with MOPD1 have been reported to show profound, life-limiting clinical decompensation at the time of a febrile illness, these episodes including magnetic resonance imaging (MRI) findings have not been well characterized. We present acute MRI brain findings for a 10-year-old girl with homozygous variants in RNU4ATAC (NR_023343.1) n.55G>A, who presented with two episodes of clinical decompensation associated with a febrile illness in early childhood. The pathogenic variants were identified by whole genome sequencing as RNU4ATAC is not captured in most exome products. Her MRI of the brain revealed symmetric, diffusion restriction of the deep gray nuclei that initially pointed to a mitochondrial disease or acute necrotizing encephalopathy. Her phenotype included microcephaly and profound cognitive impairment that can be seen with MOPD1. However, she did not demonstrate clinical or radiographic evidence of a spondyloepimetaphyseal dysplasia or "primordial dwarfism" that is characteristic of this disease. As such, the predominant neurological presentation of this child represents an atypical variant of RNU4ATAC-associated disease and should be a diagnostic consideration for geneticists and neurologists caring for children, particularly in the event of an acute clinical decline.
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- 2021
8. Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data
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Taila, Hartley, Élisabeth, Soubry, Meryl, Acker, Matthew, Osmond, Madeline, Couse, Meredith K, Gillespie, Yoko, Ito, Aren E, Marshall, Gabrielle, Lemire, Lijia, Huang, Caitlin, Chisholm, Alison J, Eaton, E Magda, Price, James J, Dowling, Arun K, Ramani, Roberto, Mendoza-Londono, Gregory, Costain, Michelle M, Axford, Anna, Szuto, Vanda, McNiven, Nadirah, Damseh, Rebekah, Jobling, Leanne, de Kock, Bahareh A, Mojarad, Ted, Young, Zhuo, Shao, Robin Z, Hayeems, Ian D, Graham, Mark, Tarnopolsky, Lauren, Brady, Christine M, Armour, Michael, Geraghty, Julie, Richer, Sarah, Sawyer, Matthew, Lines, Saadet, Mercimek-Andrews, Melissa T, Carter, Gail, Graham, Peter, Kannu, Joanna, Lazier, Chumei, Li, Ritu B, Aul, Tugce B, Balci, Nomazulu, Dlamini, Lauren, Badalato, Andrea, Guerin, Jagdeep, Walia, David, Chitayat, Ronald, Cohn, Hanna, Faghfoury, Cynthia, Forster-Gibson, Hernan, Gonorazky, Eyal, Grunebaum, Michal, Inbar-Feigenberg, Natalya, Karp, Chantal, Morel, Alison, Rusnak, Neal, Sondheimer, Jodi, Warman-Chardon, Priya T, Bhola, Danielle K, Bourque, Inara J, Chacon, Lauren, Chad, Pranesh, Chakraborty, Karen, Chong, Asif, Doja, Elaine Suk-Ying, Goh, Maha, Saleh, Beth K, Potter, Christian R, Marshall, David A, Dyment, Kristin, Kernohan, and Kym M, Boycott
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Genetics ,Genetics (clinical) - Abstract
We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.
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- 2022
9. Care4Rare Canada: Outcomes from a decade of network science for rare disease gene discovery
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Kym M. Boycott, Taila Hartley, Kristin D. Kernohan, David A. Dyment, Heather Howley, A. Micheil Innes, Francois P. Bernier, and Michael Brudno
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Canada ,Rare Diseases ,Exome Sequencing ,Perspective ,Genetics ,Humans ,Exome ,Genetics (clinical) ,Genetic Association Studies - Abstract
The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.
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- 2022
10. Seven years since the launch of the Matchmaker Exchange: The evolution of genomic matchmaking
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Kym M. Boycott, Danielle R. Azzariti, Ada Hamosh, and Heidi L. Rehm
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Phenotype ,Rare Diseases ,Information Dissemination ,Databases, Genetic ,Genetics ,Humans ,Genetic Predisposition to Disease ,Genomics ,Article ,Genetics (clinical) - Abstract
The Matchmaker Exchange (MME) was launched in 2015 to provide a robust mechanism to discover novel disease-gene relationships. It operates as a federated network connecting databases holding relevant data using a common application programming interface, where two or more users are looking for a match for the same gene (two-sided matchmaking). Seven years from its launch, it is clear that the MME is making outstanding contributions to understanding the morbid anatomy of the genome. The number of unique genes present across the MME has steadily increased over time; there are currently >13,520 unique genes (~68% of all protein coding genes) connected across the MME’s eight genomic matchmaking nodes, GeneMatcher, DECIPHER, PhenomeCentral, MyGene2, seqr, Initiative on Rare and Undiagnosed Disease, PatientMatcher, and the RD-Connect Genome-Phenome Analysis Platform. The collective dataset accessible across the MME currently includes more than 120,000 cases from over 12,000 contributors in 98 countries. The discovery of potential new disease-gene relationships is happening daily and international collaborative teams are moving these connections forward to publication, now numbering well over 500. Expansion of data sharing into routine clinical practice by clinicians, genetic counselors and clinical laboratories has ensured access to discovery for even more individuals with undiagnosed rare genetic disease. Tens of thousands of patients and their family members have been directly or indirectly impacted by the discoveries facilitated by two-sided genomic matchmaking. MME supports further connections to the literature (PubCaseFinder) and to human and model organism resources (Monarch Initiative) and scientists (ModelMatcher). Efforts are now underway to explore additional approaches to matchmaking at the gene or variant level where there is only one querier (one-sided matchmaking). Genomic matchmaking has proven its utility over the past 7 years and will continue to facilitate discoveries in the years to come.
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- 2022
11. Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies
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Corinne Holubowich, Wendy J. Ungar, Irfan A. Dhalla, Kym M. Boycott, Nancy Sikich, Elaine Suk-Ying Goh, Chunmei Li, Stacey Vandersluis, and Vivian Ng
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Cost effectiveness ,Cost-Benefit Analysis ,Developmental Disabilities ,030105 genetics & heredity ,Genome ,DNA sequencing ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Abnormalities, Multiple ,Medical diagnosis ,Child ,health care economics and organizations ,Genetics (clinical) ,Exome sequencing ,Genetic testing ,Ontario ,medicine.diagnostic_test ,business.industry ,030104 developmental biology ,Active treatment ,Genetic diagnosis ,business - Abstract
Purpose Genetic testing is routine practice for individuals with unexplained developmental disabilities and multiple congenital anomalies. However, current testing pathways can be costly and time consuming, and the diagnostic yield low. Genome-wide sequencing, including exome sequencing (ES) and genome sequencing (GS), can improve diagnosis, but at a higher cost. This study aimed to assess the cost-effectiveness of genome-wide sequencing in Ontario, Canada. Methods A cost-effectiveness analysis was conducted using a discrete event simulation from a public payer perspective. Six strategies involving ES or GS were compared. Outcomes reported were direct medical costs, number of molecular diagnoses, number of positive findings, and number of active treatment changes. Results If ES was used as a second-tier test (after the current first-tier, chromosomal microarray, fails to provide a diagnosis), it would be less costly and more effective than standard testing (CAN$6357 [95% CI: 6179-6520] vs. CAN$8783 per patient [95% CI: 2309-31,123]). If ES was used after standard testing, it would cost an additional CAN$15,228 to identify the genetic diagnosis for one additional patient compared with standard testing. The results remained robust when parameters and assumptions were varied. Conclusion ES would likely be cost-saving if used earlier in the diagnostic pathway.
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- 2021
12. Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53
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Jennifer L. Fish, Kym M. Boycott, Fjodor Merkuri, Peter C. Stirling, Rachel Aber, Matthew A. Lines, Eric Bareke, Marie-Claude Beauchamp, Anissa Djedid, Loydie A. Jerome-Majewska, Annie S. Tam, and Jacek Majewski
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Microcephaly ,Biology ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Humans ,Craniofacial ,Molecular Biology ,Ribonucleoprotein, U5 Small Nuclear ,Genetics (clinical) ,Sequence Deletion ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,Homozygote ,Alternative splicing ,Neural crest ,Proto-Oncogene Proteins c-mdm2 ,General Medicine ,Peptide Elongation Factors ,medicine.disease ,Exon skipping ,Cell biology ,Mutation ,RNA splicing ,General Article ,Tumor Suppressor Protein p53 ,030217 neurology & neurosurgery - Abstract
EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells. Homozygous deletion of Eftud2 causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3. Exon skipping in Mdm2 was also increased in O9-1 mouse neural crest cells after siRNA knock-down of Eftud2 and in MFDM patient cells. Moreover, we found increased nuclear P53, higher expression of P53-target genes and increased cell death. Finally, overactivation of the P53 pathway in Eftud2 knockdown cells was attenuated by overexpression of non-spliced Mdm2, and craniofacial development was improved when Eftud2-mutant embryos were treated with Pifithrin-α, an inhibitor of P53. Thus, our work indicates that the P53-pathway can be targeted to prevent craniofacial abnormalities and shows a previously unknown role for alternative splicing of Mdm2 in the etiology of MFDM.
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- 2021
13. Correction to: Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia
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Lijia Huang, Jodi Warman-Chardon, Melissa T. Carter, Kathie L. Friend, Tracy E. Dudding, Jeremy Schwartzentruber, Ruobing Zou, Peter W. Schofield, Stuart Douglas, Dennis E. Bulman, and Kym M. Boycott
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Pharmacology (medical) ,General Medicine ,Genetics (clinical) - Published
- 2022
14. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in <scp> PIGQ </scp> : Report of seven new subjects and review of the literature
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Rebecca C. Spillmann, Nissan V. Baratang, Kym M. Boycott, Karen W. Gripp, Taila Hartley, Anik St-Denis, Philippe M. Campeau, Kristin D. Kernohan, Erik A. Eklund, Jessica L. Zambonin, Loren D M Pena, Michael T. Geraghty, Andrew C. Edmondson, Jacek Majewski, Hugh J. McMillan, Allan Bayat, Miao He, Manuela Pendziwiat, Eric Bareke, Andrea Guerin, Thi Tuyet Mai Nguyen, Julie Richer, Devon L. Johnstone, and Hilde M. H. Braakman
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HYPERPHOSPHATASIA ,Male ,GLYCOSYLPHOSPHATIDYLINOSITOL ,Disease ,Immunoglobulin D ,Fatal Outcome ,0302 clinical medicine ,1ST STEP ,PIGQ ,Child ,Genetics (clinical) ,Exome sequencing ,0303 health sciences ,biology ,medicine.diagnostic_test ,rare diseases ,DEFECTS ,Transfection ,Phenotype ,3. Good health ,epileptic encephalopathy ,Child, Preschool ,Muscle Hypotonia ,Original Article ,Female ,medicine.symptom ,Spasms, Infantile ,DISORDERS ,Mutation, Missense ,Status epilepticus ,Flow cytometry ,03 medical and health sciences ,Seizures ,Exome Sequencing ,Genetics ,medicine ,Humans ,BIOSYNTHESIS ,Abnormalities, Multiple ,IGD ,Gene ,030304 developmental biology ,MUTATIONS ,business.industry ,Infant, Newborn ,Infant ,Membrane Proteins ,Original Articles ,GENE ,GPI ,Immunology ,biology.protein ,business ,exome sequencing ,030217 neurology & neurosurgery - Abstract
We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)‐anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ‐related disease and provide the first functional evidence in human cells of defective GPI‐anchoring due to pathogenic variants in PIGQ.
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- 2020
15. Outcome of over 1500 matches through the Matchmaker Exchange for rare disease gene discovery: The 2-year experience of Care4Rare Canada
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Matthew Osmond, Taila Hartley, David A. Dyment, Kristin D. Kernohan, Michael Brudno, Orion J. Buske, A. Micheil Innes, Kym M. Boycott, Kym Boycott, Francois Bernier, Clara van Karnebeek, David Dyment, Kristin Kernohan, Micheil Innes, Ryan Lamont, Jillian Parboosingh, Deborah Marshall, Christian Marshall, Roberto Mendoza, James Dowling, Robin Hayeems, Bartha Knoppers, Anna Lehman, Sara Mostafavi, VU University medical center, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, and Paediatrics
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Canada ,0303 health sciences ,Information Dissemination ,GeneMatcher ,Matchmaker exchange ,Rare diseases ,PhenomeCentral ,03 medical and health sciences ,Phenotype ,0302 clinical medicine ,Databases, Genetic ,Humans ,Data sharing ,Genetic Association Studies ,030217 neurology & neurosurgery ,Genetics (clinical) ,030304 developmental biology - Abstract
Purpose: Matchmaking has emerged as a useful strategy for building evidence toward causality of novel disease genes in patients with undiagnosed rare diseases. The Matchmaker Exchange (MME) is a collaborative initiative that facilitates international data sharing for matchmaking purposes; however, data on user experience is limited. Methods: Patients enrolled as part of the Finding of Rare Disease Genes in Canada (FORGE) and Care4Rare Canada research programs had their exome sequencing data reanalyzed by a multidisciplinary research team over a 2-year period. Compelling variants in genes not previously associated with a human phenotype were submitted through the MME node PhenomeCentral, and outcomes were collected. Results: In this study, 194 novel candidate genes were submitted to the MME, resulting in 1514 matches, and 15% of the genes submitted resulted in collaborations. Most submissions resulted in at least 1 match, and most matches were with GeneMatcher (82%), where additional email exchange was required to evaluate the match because of the lack of phenotypic or inheritance information. Conclusion: Matchmaking through the MME is an effective way to investigate novel candidate genes; however, it is a labor-intensive process. Engagement from the community to contribute phenotypic, genotypic, and inheritance data will ensure that matchmaking continues to be a useful approach in the future.
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- 2022
16. Novel Homozygous Variant inCOQ7in Siblings With Hereditary Motor Neuropathy
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Ian C. Smith, Chantal A. Pileggi, Ying Wang, Kristin Kernohan, Taila Hartley, Hugh J. McMillan, Marcos Loreto Sampaio, Gerd Melkus, John Woulfe, Gaganvir Parmar, Pierre R. Bourque, Ari Breiner, Jocelyn Zwicker, C. Elizabeth Pringle, Olga Jarinova, Hanns Lochmüller, David A. Dyment, Bernard Brais, Kym M. Boycott, Siegfried Hekimi, Mary-Ellen Harper, and Jodi Warman-Chardon
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Neurology (clinical) ,Genetics (clinical) - Abstract
Background and ObjectivesCoenzyme Q10(CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant ofCOQ7with abnormal CoQ10biosynthesis.MethodsAffected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of theCOQ7variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis.ResultsThree affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygousCOQ7c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of theCOQ7variant was demonstrated by diminished COQ7 and CoQ10levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle.DiscussionThis report describes a new neurologic phenotype ofCOQ7-related primary CoQ10deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases ofCOQ7-related CoQ10deficiency previously reported in the literature.
- Published
- 2023
17. Whole genome sequencing reveals biallelic <scp> PLA2G6 </scp> mutations in siblings with cerebellar atrophy and cap myopathy
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Jean Michaud, Sunita Venkateswaran, David A. Dyment, Arun K. Ramani, Christian R. Marshall, Kym M. Boycott, Jodi Warman-Chardon, Kristin D. Kernohan, Hugh J. McMillan, Aren E Marshall, and Taila Hartley
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Whole genome sequencing ,Genetics ,Text mining ,business.industry ,Cerebellar atrophy ,Biology ,business ,Cap myopathy ,Genetics (clinical) - Published
- 2021
18. PhenomeCentral: 7 years of rare disease matchmaking
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Matthew Osmond, Taila Hartley, Brittney Johnstone, Sasha Andjic, Marta Girdea, Meredith Gillespie, Orion Buske, Sergiu Dumitriu, Veronika Koltunova, Arun Ramani, Kym M. Boycott, and Michael Brudno
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Phenotype ,Rare Diseases ,Genotype ,Information Dissemination ,Genetics ,Humans ,Genomics ,Genetics (clinical) - Abstract
A major challenge in validating genetic causes for patients with rare diseases (RDs) is the difficulty in identifying other RD patients with overlapping phenotypes and variants in the same candidate gene. This process, known as matchmaking, requires robust data sharing solutions in order to be effective. In 2014 we launched PhenomeCentral, a RD data repository capable of collecting computer-readable genotypic and phenotypic data for the purposes of RD matchmaking. Over the past 7 years PhenomeCentral’s features have been expanded and its dataset has consistently grown. There are currently 1,615 users registered on PhenomeCentral, which have contributed over 12,000 patient cases. Most of these cases contain detailed phenotypic terms, with a significant portion also providing genomic sequence data or other forms of clinical information. Matchmaking within PhenomeCentral, and with connections to other data repositories in the Matchmaker Exchange, have collectively resulted in over 60,000 matches, which have facilitated multiple gene discoveries. The collection of deep phenotypic and genotypic data has also positioned PhenomeCentral well to support next generation of matchmaking initiatives that utilize genome sequencing data, ensuring that PhenomeCentral will remain a useful tool in solving undiagnosed RD cases in the years to come.
- Published
- 2021
19. ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies
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Aren E Marshall, Nadie Rioux, Adrie D Dane, Tipu Sultan, Kristin D. Kernohan, Nataly Laflamme, Lauren Brady, Cynthia J. Curry, Taila Hartley, Kym M. Boycott, Nicolas Chrestian, Alexa Derksen, Frédéric M. Vaz, Maha S. Zaki, Geneviève Bernard, Joseph G. Gleeson, Gabrielle Lemire, Yoko Ito, H. T. Hutchison, Wendy Mears, Lynn Pais, Mark A. Tarnopolsky, Valentina Stanley, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Personalized Medicine, and APH - Methodology
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Adult ,Male ,Adolescent ,lysophosphatidylserine ,Hereditary spastic paraplegia ,Central nervous system ,Corpus callosum ,Bioinformatics ,White matter ,Cohort Studies ,Young Adult ,Leukoencephalopathies ,Report ,Intellectual disability ,Genetics ,Medicine ,Humans ,Global developmental delay ,hereditary spastic paraplegia ,Child ,Genetics (clinical) ,business.industry ,Spastic Paraplegia, Hereditary ,Cerebral Palsy ,ABHD16A ,medicine.disease ,Monoacylglycerol Lipases ,Pedigree ,medicine.anatomical_structure ,Phenotype ,intellectual disability ,Child, Preschool ,Mutation ,Etiology ,Progressive spasticity ,Female ,business - Abstract
ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.
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- 2021
20. Homozygous WNT9B variants in two families with bilateral renal agenesis/hypoplasia/dysplasia
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Joseph de Nanassy, Chunyan Wang, Kristin D. Kernohan, Ruobing Zou, Gabrielle Lemire, Bryan Lo, Priya T. Bhola, Shirlee Shril, Caitlin Chisholm, Sherif El Desoky, Sarah L. Sawyer, Grace U Ediae, Jameela A. Kari, Kym M. Boycott, Bixia Zheng, Friedhelm Hildebrandt, Xueqi Wang, and Mohammed Shalaby
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0301 basic medicine ,Proband ,Male ,Pathology ,medicine.medical_specialty ,030105 genetics & heredity ,Kidney ,Renal tubule morphogenesis ,Article ,Congenital Abnormalities ,03 medical and health sciences ,Mice ,Pregnancy ,Genetics ,medicine ,Animals ,Humans ,Child ,Urinary Tract ,Renal agenesis ,Genetics (clinical) ,business.industry ,Homozygote ,Infant ,medicine.disease ,Renal hypoplasia ,Hypoplasia ,Bilateral Renal Agenesis ,Wnt Proteins ,030104 developmental biology ,Kidney Tubules ,Dysplasia ,Agenesis ,Urogenital Abnormalities ,Female ,Kidney Diseases ,business - Abstract
WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. To our knowledge, WNT9B has not been associated with renal defects in humans; however, WNT9B(−/−) mice have renal agenesis/hypoplasia and reproductive tract abnormalities. We report four individuals from two unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 has bilateral renal cystic dysplasia and chronic kidney disease. He has two deceased siblings who presented with bilateral renal hypoplasia/agenesis. The three affected family members were homozygous for a missense variant in WNT9B (NM_003396.2: c.949G>A/p.(Gly317Arg)). The proband from Family 2 has renal hypoplasia/dysplasia, chronic kidney disease, and is homozygous for a nonsense variant in WNT9B (NM_003396.2: c.11dupC/p.(Pro5Alafs*52)). Two of her siblings died in the neonatal period, one confirmed to be in the context of oligohydramnios. The proband’s unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting non-penetrance. We propose a novel association of WNT9B and renal anomalies in humans. Further study is needed to delineate the contribution of WNT9B to genitourinary anomalies in humans.
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- 2021
21. <scp>SMG9</scp> ‐deficiency syndrome caused by a homozygous missense variant: Expanding the genotypic and phenotypic spectrum of this developmental disorder
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Kym M. Boycott, Gabrielle Lemire, and Stella K MacDonald
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Genetics ,0303 health sciences ,Deficiency syndrome ,030305 genetics & heredity ,Biology ,medicine.disease ,Phenotype ,Developmental disorder ,03 medical and health sciences ,Mutation (genetic algorithm) ,Genotype ,medicine ,Missense mutation ,Genetics (clinical) ,030304 developmental biology - Published
- 2020
22. Correspondence on 'cost or price of sequencing? implications for economic evaluations in genomic medicine' by Grosse and Gudgeon
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Stacey Vandersluis, Irfan A. Dhalla, Nancy Sikich, Corinne Holubowich, Vivian Ng, Wendy J. Ungar, Elaine Suk-Ying Goh, Kym M. Boycott, and Chunmei Li
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Genomic medicine ,Computational biology ,Biology ,Genetics (clinical) - Published
- 2022
23. Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities
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Jennifer A. Lee, Carlos Ferreira, Kym M. Boycott, Lina Basel-Salmon, Yue Si, Richard E. Person, Michael J. Lyons, Melissa T. Carter, Dmitriy Niyazov, Claudia Gonzaga-Jauregui, Renee Bend, Erin Torti, Lior Cohen, Samantha K Rojas, Ingrid M. Wentzensen, and Mohamad A. Mikati
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Male ,Microcephaly ,Adolescent ,Biology ,medicine.disease_cause ,Compound heterozygosity ,Article ,03 medical and health sciences ,Atrophy ,Genetics ,medicine ,Humans ,DNA sequencing ,Allele ,Child ,10. No inequality ,Genetics (clinical) ,Loss function ,0303 health sciences ,Mutation ,Neurodevelopmental disorders ,Medical genetics ,030305 genetics & heredity ,Brain ,Infant ,Protein Tyrosine Phosphatases, Non-Receptor ,medicine.disease ,Phenotype ,Child, Preschool ,Female ,Ventriculomegaly - Abstract
PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.
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- 2019
24. Direct health-care costs for children diagnosed with genetic diseases are significantly higher than for children with other chronic diseases
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Taila Hartley, Alison B. Hamilton, Heather E Howley, Daniel Rodriguez Duque, Faheem Malam, Deborah A. Marshall, Meredith K. Gillespie, Eric I Benchimol, Kym M. Boycott, Karen V. MacDonald, and Alex MacKenzie
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0301 basic medicine ,education.field_of_study ,Pediatrics ,medicine.medical_specialty ,business.industry ,Total cost ,Population ,Retrospective cohort study ,Disease ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030225 pediatrics ,Diabetes mellitus ,Cohort ,Health care ,medicine ,education ,business ,health care economics and organizations ,Genetics (clinical) ,Asthma - Abstract
We aimed to estimate direct health-care costs and physician utilization for a cohort of children diagnosed with genetic diseases. Retrospective cohort study using population-based provincial health administrative data for children with genetic diseases (n = 255) compared with three matched cohorts (asthma n = 1275, diabetes n = 255, general population n = 1275). We estimated direct health-care costs and resource use 5 years after diagnosis in five categories: physician billing, same day surgery, emergency, inpatient hospitalizations, and home care. During the postdiagnostic period, annual mean total costs for the genetic disease cohort were significantly higher than all other cohorts. Annual mean total costs for all cohorts were highest in the year after diagnosis with costs for the genetic disease cohort between 4.54 and 19.76 times higher during the 5 years. Inpatient hospitalizations and physician billing accounted for the majority of costs. The genetic disease cohort received more care from specialists, whereas the chronic disease cohorts received more care from general practitioners. Direct health-care costs for children with genetic diseases are significantly higher than children with/without a chronic disease, particularly in the year after diagnosis. These findings are important when considering resource allocation and funding prioritization for children with genetic diseases.
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- 2019
25. Clinical delineation of GTPBP2 ‐associated neuro‐ectodermal syndrome: Report of two new families and review of the literature
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Kym M. Boycott, Sunita Venkateswaran, Peter Humphreys, Gali Shapira-Zaltsberg, Jorge Davila, Melissa T. Carter, and Kristin D. Kernohan
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0301 basic medicine ,Microcephaly ,Ectodermal dysplasia ,Movement disorders ,media_common.quotation_subject ,Nonsense ,Context (language use) ,030105 genetics & heredity ,Compound heterozygosity ,Bioinformatics ,03 medical and health sciences ,Epilepsy ,GTP-Binding Proteins ,Ectoderm ,Exome Sequencing ,Genetics ,medicine ,Humans ,Family ,Genetics (clinical) ,media_common ,business.industry ,Syndrome ,medicine.disease ,3. Good health ,030104 developmental biology ,Peripheral neuropathy ,medicine.symptom ,business - Abstract
The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.
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- 2019
26. Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis
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Eric Bareke, David Grynspan, Jean Michaud, Danielle K Bourque, Mireille Cloutier, Kristin D. Kernohan, and Kym M. Boycott
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0301 basic medicine ,Arthrogryposis ,Microcephaly ,Pathology ,medicine.medical_specialty ,business.industry ,Cystic hygroma ,Prenatal diagnosis ,030105 genetics & heredity ,medicine.disease ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Lymphangioma ,Genetics ,medicine ,Neu-Laxova syndrome ,medicine.symptom ,business ,Increased nuchal translucency ,Genetics (clinical) ,Exome sequencing - Abstract
Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.
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- 2019
27. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes
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Zejuan Li, Erin Sandford, Viswateja Nelakuditi, Miao Sun, Kym M. Boycott, Jodi Warman Chardon, Lan Ma, Daniela del Gaudio, Vikram G. Shakkottai, Kelly Arndt, Soma Das, David Fischer, Darrel Waggoner, Lucia Guidugli, Margit Burmeister, Christopher M. Gomez, and Amy K. Johnson
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Ataxia ,business.industry ,Disease ,030105 genetics & heredity ,Human genetics ,03 medical and health sciences ,030104 developmental biology ,Internal medicine ,Molecular genetics ,Etiology ,Medicine ,medicine.symptom ,business ,Exome ,Genetics (clinical) ,ADCK3 ,Exome sequencing - Abstract
To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions. Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions. Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.
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- 2019
28. A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome
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Kristin D. Kernohan, Sara Ellingwood, Jaime Barea, Christoffer Nellåker, Simon Sadedin, Katrin Õunap, Taila Hartley, Margarete Koch-Hogrebe, Marjan M. Nezarati, Augusta M. A. Lachmeijer, Dagmar Wieczorek, Elizabeth J. Bhoj, Paul J. Lockhart, Kym M. Boycott, Aren E Marshall, Tiong Yang Tan, Sander Pajusalu, Arran McBride, John Christodoulou, Michelle E. Ernst, Alison S May, Rami Abou Jamra, Susan M. White, Dong Li, K.L.I. van Gassen, and Wendy E. Smith
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Male ,Adolescent ,DNA Repair ,DNA damage ,DNA repair ,medicine.disease_cause ,Chromatin remodeling ,03 medical and health sciences ,DDB1 ,Report ,Histone methylation ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Alleles ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,030305 genetics & heredity ,Syndrome ,Hypotonia ,Ubiquitin ligase ,DNA-Binding Proteins ,Phenotype ,Neurodevelopmental Disorders ,Child, Preschool ,biology.protein ,Female ,medicine.symptom - Abstract
The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.
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- 2021
29. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
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Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output
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0301 basic medicine ,SHARP ,Male ,obesity ,genotype-phenotype correlations ,Autism Spectrum Disorder ,PROTEIN ,Chromosome Disorders ,Haploinsufficiency ,RNA-Binding Protein ,PHENOTYPE CORRELATIONS ,1p36 ,distal 1p36 deletion syndrome ,DNA methylome analysis ,episignature ,neurodevelopmental disorder ,proximal 1p36 deletion syndrome ,SPEN ,X chromosome ,Adolescent ,Child ,Child, Preschool ,Chromosome Deletion ,Chromosomes, Human, Pair 1 ,Chromosomes, Human, X ,DNA Methylation ,DNA-Binding Proteins ,Epigenesis, Genetic ,Female ,Humans ,Intellectual Disability ,Neurodevelopmental Disorders ,Phenotype ,RNA-Binding Proteins ,Young Adult ,0302 clinical medicine ,Neurodevelopmental disorder ,Neurodevelopmental Disorder ,Intellectual disability ,MOLECULAR CHARACTERIZATION ,Genetics (clinical) ,Genetics ,DNA methylome analysi ,SPLIT-ENDS ,Hypotonia ,Autism spectrum disorder ,MONOSOMY 1P36 ,Pair 1 ,medicine.symptom ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Human ,DNA-Binding Protein ,Biology ,genotype-phenotype correlation ,Chromosomes ,03 medical and health sciences ,Genetic ,SDG 3 - Good Health and Well-being ,Report ,REVEALS ,medicine ,Epigenetics ,Preschool ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,1p36 deletion syndrome ,IDENTIFICATION ,MUTATIONS ,medicine.disease ,GENE ,030104 developmental biology ,Chromosome Disorder ,030217 neurology & neurosurgery ,Epigenesis - Abstract
Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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- 2021
30. Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development
- Author
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Christopher Kelly, Brenda J. Barry, Kym M. Boycott, Wai-Man Chan, Daniel G. MacArthur, Sarah MacKinnon, Julie Jurgens, Anne H. O’Donnell-Luria, Hugh J. McMillan, David G. Hunter, Mary C. Whitman, Sherin Shaaban, Brandon M Pratt, Gabrielle Lemire, Elizabeth C. Engle, Eleina M. England, and Caroline D. Robson
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Proband ,Male ,Heterozygote ,Adolescent ,Mutation, Missense ,Kinesins ,Biology ,DNA sequencing ,Article ,Lateral ventricles ,Tubulin ,Congenital fibrosis of the extraocular muscles ,Genetics ,medicine ,Missense mutation ,Humans ,Child ,Gene ,Genetics (clinical) ,Exome sequencing ,TUBB3 ,Binding Sites ,Ophthalmoplegia ,medicine.disease ,Fibrosis ,Malformations of Cortical Development ,Female - Abstract
Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.
- Published
- 2021
31. Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome
- Author
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Sixto Garcia Minaur, Pankaj B. Agrawal, A. Micheil Innes, Catherine A. Brownstein, David S. Wargowski, Brenda McInnes, Isaac Wong, Albert E. Chudley, Jennifer E. Posey, Francesc López-Giráldez, Ping-Yee B Au, Alper Gezdirici, Kyrieckos A. Aleck, Eric Boerwinkle, Paolo Prontera, Bilgen Bilge Geçkinli, Yeting Zhang, An Nguyen, David A. Dyment, Jukka S. Moilanen, Alan H. Beggs, Nara Sobreira, Hatip Aydin, Elizabeth E. Blue, Kathryn Dunn, Gerald F. Cox, Bernard N. Chodirker, Harrison Brand, Jinchuan Xing, Hind Al Sharhan, Bert B.A. de Vries, Maria Juliana Rodovalho Doriqui, Davut Pehlivan, Shalini N. Jhangiani, Centers for Mendelian Genomics, Katrin Õunap, Cheryl R. Greenberg, Kaya Bilguvar, Carol L. Clericuzio, Cynthia J. Curry, Taila Hartley, Julie Lauzon, Michael J. Bamshad, Timothy Poterba, R. Brian Lowry, Jill A. Fahrner, Cullen M. Dutmer, M. E. Suzanne Lewis, Steve Buyske, Ender Karaca, Aziz Mhanni, William T. Gibson, Valentina Stanley, April Hall, Elke de Boer, Kristin D. Kernohan, Joseph G. Gleeson, P. Dane Witmer, Jungmin Choi, Danny Antaki, Małgorzata J.M. Nowaczyk, Sander Pajusalu, Anne H. O’Donnell-Luria, Sarah L. Sawyer, Zeynep Coban Akdemir, Tara C. Matise, Jennifer McEvoy-Venneri, Casie A. Genetti, Kym M. Boycott, Lynette S. Penney, Ada Hamosh, Eleina M. England, Deniz Torun, Maha S. Zaki, Deborah A. Nickerson, Dyment, David A., O'Donnell-Luria, Anne, Agrawal, Pankaj B., Coban Akdemir, Zeynep, Aleck, Kyrieckos A., Antaki, Danny, Al Sharhan, Hind, Au, Ping-Yee B., Aydin, Hatip, Beggs, Alan H., Bilguvar, Kaya, Boerwinkle, Eric, Brand, Harrison, Brownstein, Catherine A., Buyske, Steve, Chodirker, Bernard, Choi, Jungmin, Chudley, Albert E., Clericuzio, Carol L., Cox, Gerald F., Curry, Cynthia, de Boer, Elke, de Vries, Bert B. A., Dunn, Kathryn, Dutmer, Cullen M., England, Eleina M., Fahrner, Jill A., Geckinli, Bilgen B., Genetti, Casie A., Gezdirici, Alper, Gibson, William T., Gleeson, Joseph G., Greenberg, Cheryl R., Hall, April, Hamosh, Ada, Hartley, Taila, Jhangiani, Shalini N., Karaca, Ender, Kernohan, Kristin, Lauzon, Julie L., Lewis, M. E. Suzanne, Lowry, R. Brian, Lopez-Giraldez, Francesc, Matise, Tara C., McEvoy-Venneri, Jennifer, McInnes, Brenda, Mhanni, Aziz, Garcia Minaur, Sixto, Moilanen, Jukka, Nguyen, An, Nowaczyk, Malgorzata J. M., Posey, Jennifer E., Ounap, Katrin, Pehlivan, Davut, Pajusalu, Sander, Penney, Lynette S., Poterba, Timothy, Prontera, Paolo, Doriqui, Maria Juliana Rodovalho, Sawyer, Sarah L., Sobreira, Nara, Stanley, Valentina, Torun, Deniz, Wargowski, David, Witmer, P. Dane, Wong, Isaac, Xing, Jinchuan, Zaki, Maha S., Zhang, Yeting, Boycott, Kym M., Bamshad, Michael J., Nickerson, Deborah A., Blue, Elizabeth E., and Innes, A. Micheil
- Subjects
0301 basic medicine ,Male ,ANOMALIES ,INTELLECTUAL DISABILITY ,Eczema ,030105 genetics & heredity ,PHENOTYPE ,genetic heterogeneity ,Locus heterogeneity ,Dubowitz syndrome ,Exome ,Child ,Genetics (clinical) ,Exome sequencing ,Growth Disorders ,Genetics ,FRAMESHIFT ,Genomics ,3. Good health ,VPS13B ,genome sequencing ,LOSS-OF-FUNCTION ,Child, Preschool ,symbols ,Microcephaly ,Female ,microarray ,Adolescent ,DNA Copy Number Variations ,Biology ,NSUN2 ,PATIENT ,DNA sequencing ,Histone Deacetylases ,Article ,03 medical and health sciences ,symbols.namesake ,medicine ,Humans ,Genetic Predisposition to Disease ,ANEMIA ,Genetic heterogeneity ,Genome, Human ,MUTATIONS ,Facies ,Infant ,PLATFORM ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Mendelian inheritance ,exome sequencing - Abstract
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
- Published
- 2021
32. The International Rare Diseases Research Consortium : Policies and Guidelines to maximize impact
- Author
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Anneliene H. Jonker, Yann Le Cam, Josep Torrent i Farnell, Gareth Baynam, Hugh Dawkins, Christopher P. Austin, Lilian P.L. Lau, Hanns Lochmüller, Paul Lasko, Kym M. Boycott, and Petra Kaufmann
- Subjects
0301 basic medicine ,business.industry ,International Cooperation ,Environmental resource management ,Guidelines as Topic ,Human Genetics ,030105 genetics & heredity ,Intellectual property ,Public relations ,Medical research ,Biobank ,Transparency (behavior) ,Article ,3. Good health ,Data sharing ,03 medical and health sciences ,Rare Diseases ,Genetics ,Humans ,Business ,Productivity ,Genetics (clinical) ,Health policy ,Rare disease - Abstract
Altres ajuts: This work and the IRDiRC Scientific Secretariat are supported by the European FP7 contract, "SUPPORT-IRDiRC" (No 305207). H.L. receives funding from the European Commission under FP7 through NeurOmics (No 305121) and RD-Connect (No 305444). C.P.A. contributed to this work in his capacity as Chair of the IRDiRC Consortium Assembly, not as Director of the NCATS. The remaining authors declare that they have no competing interests. The International Rare Diseases Research Consortium (IRDiRC) has agreed on IRDiRC Policies and Guidelines, following extensive deliberations and discussions in 2012 and 2013, as a first step towards improving coordination of research efforts worldwide. The 25 funding members and 3 patient umbrella organizations (as of early 2013) of IRDiRC, a consortium of research funders that focuses on improving diagnosis and therapy for rare disease patients, agreed in Dublin, Ireland in April 2013 on the Policies and Guidelines that emphasize collaboration in rare disease research, the involvement of patients and their representatives in all relevant aspects of research, as well as the sharing of data and resources. The Policies and Guidelines provide guidance on ontologies, diagnostics, biomarkers, patient registries, biobanks, natural history, therapeutics, models, publication, intellectual property, and communication. Most IRDiRC members-currently nearly 50 strong-have since incorporated its policies in their funding calls and some have chosen to exceed the requirements laid out, for instance in relation to data sharing. The IRDiRC Policies and Guidelines are the first, detailed agreement of major public and private funding organizations worldwide to govern rare disease research, and may serve as a template for other areas of international research collaboration. While it is too early to assess their full impact on research productivity and patient benefit, the IRDiRC Policies and Guidelines have already contributed significantly to improving transparency and collaboration in rare disease research.
- Published
- 2021
33. Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans
- Author
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Mais Hashem, Moeenaldeen Al-Sayed, Mohamed H Al-Hamed, Maha Alnemer, Wenkai Han, Mohamed Tohary, Yongkang Long, Almundher Al-Maawali, Feisal Al Mahrizi, Xin Gao, Khalid Al-Thihli, Fowzan S. Alkuraya, Hiroyuki Kuwahara, Gabrielle Lemire, Lana Fathi, Kym M. Boycott, Fatema Alzahrani, Mohammed Al-Owain, and Mohammed Mahnashi
- Subjects
Heart Defects, Congenital ,Male ,Microcephaly ,Adolescent ,Genetic Linkage ,Developmental Disabilities ,Nonsense-mediated decay ,RNA-Seq ,Biology ,03 medical and health sciences ,Consanguinity ,Young Adult ,0302 clinical medicine ,Report ,Intellectual disability ,Genetics ,medicine ,Humans ,Global developmental delay ,RNA, Messenger ,Kinase activity ,Phosphorylation ,Child ,Genetics (clinical) ,030304 developmental biology ,Family Health ,0303 health sciences ,Homozygote ,Intracellular Signaling Peptides and Proteins ,Brain ,Infant ,medicine.disease ,Phenotype ,Nonsense Mediated mRNA Decay ,Pedigree ,Child, Preschool ,Trans-Activators ,Female ,030217 neurology & neurosurgery ,Gene Deletion ,RNA Helicases - Abstract
Summary We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
- Published
- 2020
34. New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases
- Author
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Heather E. Howley, Taila Hartley, Kym M. Boycott, David R. Adams, Kristin D. Kernohan, and Gabrielle Lemire
- Subjects
medicine.medical_specialty ,business.industry ,Genome, Human ,Cornerstone ,Genomics ,Disease ,Data sharing ,Rare Diseases ,Genetics ,Medicine ,Humans ,business ,Intensive care medicine ,Molecular Biology ,Genetics (clinical) - Abstract
Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale.
- Published
- 2020
35. Mosaic KRAS mutation in a patient with encephalocraniocutaneous lipomatosis and renovascular hypertension
- Author
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Kym M. Boycott, Brian H.Y. Chung, Hussein Daoud, Lawrence Lan, Gordon K.C. Leung, Laura M McDonell, Ho Ming Luk, Stella Chim, and Janice Ip
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Adolescent ,Eye Diseases ,Renal Artery Obstruction ,Proto-Oncogene Mas ,Renovascular hypertension ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Lipomatosis ,Child ,Genetics (clinical) ,Base Sequence ,Mosaicism ,business.industry ,Neurocutaneous Syndromes ,medicine.disease ,Hypertension, Renovascular ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Mutation ,Encephalocraniocutaneous Lipomatosis ,Tomography, X-Ray Computed ,business ,Kras mutation - Published
- 2018
36. Is PNPT1 -related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1 -related disorders
- Author
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Caitlin Goedhart, A. Micheil Innes, Alison Eaton, Oana Caluseriu, Jillian S. Parboosingh, Ryan E. Lamont, Kym M. Boycott, and Francois P. Bernier
- Subjects
Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Ataxia ,Hearing loss ,Hearing Loss, Sensorineural ,Mitochondrial disease ,030105 genetics & heredity ,03 medical and health sciences ,Exome Sequencing ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,RNA, Messenger ,Cognitive decline ,Genetics (clinical) ,Exome sequencing ,Dystonia ,business.industry ,Siblings ,Middle Aged ,medicine.disease ,Pedigree ,Natural history ,Exoribonucleases ,Female ,Sensorineural hearing loss ,medicine.symptom ,business - Abstract
PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932). The latter has been described in multiple families presenting with complex neurologic manifestations in childhood. We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL). In their 40s, they each developed and then followed a nearly identical neurodegenerative course with ataxia, dystonia, and cognitive decline. Now in their 50s and 60s, all have developed the additional features of optic nerve atrophy, spasticity, and incontinence. The natural history of the condition in this family may suggest that the individuals previously reported as having isolated SNHL may be at risk of developing multisystem disease in late adulthood, and that PNPT1-related disorders may constitute a spectrum rather than distinct phenotypes.
- Published
- 2018
37. When to think outside the autozygome: Best practices for exome sequencing in 'consanguineous' families
- Author
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A. Micheil Innes, Yoko Ito, Alison Eaton, Jillian S. Parboosingh, Kristin D. Kernohan, Ryan E. Lamont, Taila Hartley, Nick Barrowman, and Kym M. Boycott
- Subjects
0301 basic medicine ,Male ,Canada ,Consanguinity ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Exome Sequencing ,Genetics ,medicine ,Humans ,Exome ,Genetic Testing ,Genetics (clinical) ,Exome sequencing ,Genetic testing ,medicine.diagnostic_test ,Family structure ,Significant difference ,Homozygote ,Genetic Diseases, Inborn ,Pedigree ,030104 developmental biology ,Genetics, Population ,Mutation ,Female - Abstract
Exome sequencing (ES) is an effective diagnostic tool with a high yield in consanguineous families. However, how diagnostic yield and mode of inheritance relate to family structure has not been well delineated. We reviewed ES results from families enrolled in the Care4Rare Canada research consortium with various degrees of consanguinity. We contrasted the diagnostic yield in families with parents who are second cousins or closer ("close" consanguinity) vs those more distantly related or from isolated populations ("presumed" consanguinity). We further stratified by number of affected individuals (multiple affected ["multiplex"] vs single affected [simplex]). The overall yield in 116 families was 45.7% (n = 53) with no significant difference between subgroups. Homozygous variants accounted for 100% and 75% of diagnoses in close and presumed consanguineous multiplex families, respectively. In simplex presumed consanguineous families, a striking 46.2% of diagnoses were due to de novo variants, vs only 11.8% in simplex closely consanguineous families (88.2% homozygous). Our data underscores the high yield of ES in consanguineous families and highlights that while a singleton approach may frequently be reasonable and a responsible use of resources, trio sequencing should be strongly considered in simplex families in the absence of confirmed consanguinity given the proportion of de novo variants.
- Published
- 2019
38. A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys
- Author
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Afsana Ahmed, Aimee C. Smidt, Carol L. Clericuzio, Dennis E. Bulman, Amanda C. Smith, Sara L. Sawyer, Kym M. Boycott, David A. Dyment, Laura M McDonell, Chandree L. Beaulieu, Kristin D. Kernohan, Izabella A. Pena, and Yoko Ito
- Subjects
Male ,0301 basic medicine ,Microcephaly ,Pathology ,medicine.medical_specialty ,Genes, Recessive ,Biology ,Kidney ,medicine.disease_cause ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,Global developmental delay ,Craniofacial ,Growth Disorders ,Genetics (clinical) ,Exome sequencing ,Mutation ,Facies ,Membrane Transport Proteins ,Alopecia ,medicine.disease ,Uremia ,3. Good health ,030104 developmental biology ,Child, Preschool ,Female ,Congenital Alopecia - Abstract
A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage. Three of the children died before 3 years of age from uremia and/or sepsis. Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family. In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings. ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus. Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1. Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase. We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome.
- Published
- 2018
39. The role of the clinician in the multi-omics era: are you ready?
- Author
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Carlos Ferreira, Tobias B. Haack, Kym M. Boycott, Saskia B. Wortmann, Carla E. M. Hollak, Mirjam Langeveld, Hans R. Waterham, Maja Tarailo-Graovac, Jiddeke M. van de Kamp, Wyeth W. Wasserman, Clara D.M. van Karnebeek, Ron A. Wevers, Ronald J.A. Wanders, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Reproduction & Development (AR&D), Laboratory Medicine, ANS - Complex Trait Genetics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Paediatric Metabolic Diseases, Endocrinology, Laboratory Genetic Metabolic Diseases, APH - Methodology, and ACS - Diabetes & metabolism
- Subjects
0301 basic medicine ,Epigenomics ,Male ,Proteomics ,Systems biology ,Big data ,Genomics ,Inherited Metabolic Disease ,Metabolomics ,Diagnosis ,Treatment ,Precision Medicine ,03 medical and health sciences ,Neonatal Screening ,All institutes and research themes of the Radboud University Medical Center ,Genetics ,Humans ,Capstone ,Inherited metabolic disease ,Patient participation ,Phenomics ,Physician's Role ,Glycomics ,Genetics (clinical) ,business.industry ,Systems Biology ,Precision medicine ,Infant, Newborn ,Omics ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Data science ,3. Good health ,Data sharing ,030104 developmental biology ,Molecular Diagnostic Techniques ,Female ,Psychology ,business - Abstract
Since Garrod’s first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment. While each of the -omics technologies is important to systems biology, some are more mature than others. Exome sequencing is emerging as a reimbursed test in clinics around the world, and untargeted metabolomics has the potential to serve as a single biochemical testing platform. The challenge lies in the integration and cautious interpretation of these big data, with translation into clinically meaningful information and/or action for our patients. A daunting but exciting task for the clinician; we provide clinical cases to illustrate the importance of his/her role as the connector between physicians, laboratory experts and researchers in the basic, computer, and clinical sciences. Open collaborations, data sharing, functional assays, and model organisms play a key role in the validation of -omics discoveries. Having all the right expertise at the table when discussing the diagnostic approach and individualized management plan according to the information yielded by -omics investigations (e.g., actionable mutations, novel therapeutic interventions), is the stepping stone of P4 medicine. Patient participation and the adjustment of the medical team’s plan to his/her and the family’s wishes most certainly is the capstone. Are you ready?
- Published
- 2018
40. A family segregating lethal neonatal coenzyme Q(10) deficiency caused by mutations in COQ9
- Author
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Jeremy Schwartzentruber, Chandree L. Beaulieu, Karina Horsting-Wethly, Erika Aberg, Dennis E. Bulman, Yoko Ito, Lynette S. Penney, Kym M. Boycott, Jacek Majewski, Afsana Ahmed, Diana Vermunt-de Koning, Richard J. Rodenburg, and Amanda C. Smith
- Subjects
0301 basic medicine ,Coenzyme Q10 ,medicine.medical_specialty ,Genetic heterogeneity ,business.industry ,Mitochondrial disease ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Compound heterozygosity ,medicine.disease ,3. Good health ,03 medical and health sciences ,chemistry.chemical_compound ,Exon ,030104 developmental biology ,Endocrinology ,All institutes and research themes of the Radboud University Medical Center ,chemistry ,Internal medicine ,Lactic acidosis ,Genetics ,medicine ,Leigh disease ,business ,Genetics (clinical) ,Exome sequencing - Abstract
Primary CoQ10 deficiency is a clinically and genetically heterogeneous, autosomal recessive disorder resulting from mutations in genes involved in the synthesis of coenzyme Q10 (CoQ10). To date, mutations in nine proteins required for the biosynthesis of CoQ10 cause CoQ10 deficiency with varying clinical presentations. In 2009 the first patient with mutations in COQ9 was reported in an infant with a neonatal-onset, primary CoQ10 deficiency with multi-system disease. Here we describe four siblings with a previously undiagnosed lethal disorder characterized by oligohydramnios and intrauterine growth restriction, variable cardiomyopathy, anemia, and renal anomalies. The first and third pregnancy resulted in live born babies with abnormal tone who developed severe, treatment unresponsive lactic acidosis after birth and died hours later. Autopsy on one of the siblings demonstrated brain changes suggestive of the subacute necrotizing encephalopathy of Leigh disease. Whole-exome sequencing (WES) revealed the siblings shared compound heterozygous mutations in the COQ9 gene with both variants predicted to affect splicing. RT-PCR on RNA from patient fibroblasts revealed that the c.521 + 2 T > C variant resulted in splicing out of exons 4–5 and the c.711 + 3G > C variant spliced out exon 6, resulting in undetectable levels of COQ9 protein in patient fibroblasts. The biochemical profile of patient fibroblasts demonstrated a drastic reduction in CoQ10 levels. An additional peak on the chromatogram may represent accumulation of demethoxy coenzyme Q (DMQ), which was shown previously to accumulate as a result of a defect in COQ9. This family expands our understanding of this rare metabolic disease and highlights the prenatal onset, clinical variability, severity, and biochemical profile associated with COQ9-related CoQ10 deficiencies.
- Published
- 2018
41. A novel mutation in LAMC3 associated with generalized polymicrogyria of the cortex and epilepsy
- Author
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Jillian S. Parboosingh, Kym M. Boycott, M. Kerr, Jessica L. Zambonin, Elka Miller, Yanwei Xi, Sunita Venkateswaran, Taila Hartley, Ryan E. Lamont, and David A. Dyment
- Subjects
0301 basic medicine ,Adolescent ,Nonsense mutation ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Epilepsy ,0302 clinical medicine ,Neurodevelopmental disorder ,Cortex (anatomy) ,Genetics ,medicine ,Polymicrogyria ,Humans ,Genetics (clinical) ,Pachygyria ,Brain ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Phenotype ,Human genetics ,030104 developmental biology ,medicine.anatomical_structure ,Codon, Nonsense ,Female ,Laminin ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Occipital cortical malformation is a rare neurodevelopmental disorder characterized by pachygyria and polymicrogyria of the occipital lobes as well as global developmental delays and seizures. This condition is due to biallelic, loss-of-function mutations in LAMC3 and has been reported in four unrelated families to date. We report an individual with global delays, seizures, and polymicrogyria that extends beyond the occipital lobes and includes the frontal, parietal, temporal, and occipital lobes. Next-generation sequencing identified a homozygous nonsense mutation in LAMC3: c.3190C>T (p.Gln1064*). This finding extends the cortical phenotype associated with LAMC3 mutations.
- Published
- 2017
42. Evaluation of exome filtering techniques for the analysis of clinically relevant genes
- Author
-
Taila Hartley, Najmeh Alirezaie, David A. Dyment, Peter N. Robinson, Kym M. Boycott, and Kristin D. Kernohan
- Subjects
0301 basic medicine ,In silico ,Computational Biology ,Sequence Analysis, DNA ,Computational biology ,Biology ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Databases, Genetic ,Human Phenotype Ontology ,Genetics ,OMIM : Online Mendelian Inheritance in Man ,Humans ,Exome ,University medical ,Medical diagnosis ,Gene ,Software ,Genetics (clinical) ,Exome sequencing ,Retrospective Studies - Abstract
A significant challenge facing clinical translation of exome sequencing is meaningful and efficient variant interpretation. Each exome contains ∼500 rare coding variants; laboratories must systematically and efficiently identify which variant(s) contribute to the patient's phenotype. In silico filtering is an approach that reduces analysis time while decreasing the chances of incidental findings. We retrospectively assessed 55 solved exomes using available datasets as in silico filters: Online Mendelian Inheritance in Man (OMIM), Orphanet, Human Phenotype Ontology (HPO), and Radboudumc University Medical Center curated panels. We found that personalized panels produced using HPO terms for each patient had the highest success rate (100%), while producing considerably less variants to assess. HPO panels also captured multiple diagnoses in the same individual. We conclude that custom HPO-derived panels are an efficient and effective way to identify clinically relevant exome variants.
- Published
- 2017
43. 'Matching' consent to purpose: The example of the Matchmaker Exchange
- Author
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Heidi L. Rehm, Matthew E. Hurles, Stephanie O.M. Dyke, Bartha Maria Knoppers, Kym M. Boycott, Michael Brudno, Ada Hamosh, Anthony A. Philippakis, and Helen V. Firth
- Subjects
0301 basic medicine ,Matching (statistics) ,Candidate gene ,business.industry ,Internet privacy ,Information Dissemination ,Biology ,Precision medicine ,Odds ,Data sharing ,03 medical and health sciences ,030104 developmental biology ,Data access ,Genetics ,Personalized medicine ,business ,Genetics (clinical) - Abstract
The Matchmaker Exchange (MME) connects rare disease clinicians and researchers to facilitate the sharing of data from undiagnosed patients for the purpose of novel gene discovery. Such sharing raises the odds that two or more similar patients with candidate genes in common may be found, thereby allowing their condition to be more readily studied and understood. Consent considerations for data sharing in MME included both the ethical and legal differences between clinical and research settings and the level of privacy risk involved in sharing varying amounts of rare disease patient data to enable patient matches. In this commentary, we discuss these consent considerations and the resulting MME Consent Policy as they may be relevant to other international data sharing initiatives.
- Published
- 2017
44. Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome
- Author
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S. Ordorica, E. Creede, David A. Dyment, Kym M. Boycott, L. Gallagher, D. Lahey, P. Y B Au, K. Mina, Stephanie Broley, Gareth Baynam, and L. Huang
- Subjects
0301 basic medicine ,Genetics ,Pediatrics ,medicine.medical_specialty ,Polydactyly ,General Medicine ,Scoliosis ,Biology ,medicine.disease ,Frameshift mutation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Anal atresia ,Intellectual disability ,medicine ,Etiology ,Haploinsufficiency ,030217 neurology & neurosurgery ,Genetics (clinical) ,Chromosomal inversion - Abstract
The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5′UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.
- Published
- 2017
45. Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and molecular diagnostic rates in a retrospective cohort
- Author
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Christine M. Armour, Meredith K. Gillespie, Faheem Malam, Julie Richer, Kym M. Boycott, Sarah L. Sawyer, Erika Bariciak, Sarah M. Nikkel, Taila Hartley, David A. Dyment, and Gail E. Graham
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,Neonatal intensive care unit ,business.industry ,Genetic heterogeneity ,Retrospective cohort study ,Disease ,030105 genetics & heredity ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Genetics ,medicine ,Medical genetics ,Medical diagnosis ,Differential diagnosis ,business ,Genetics (clinical) ,Exome sequencing - Abstract
Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.
- Published
- 2017
46. Whole-transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy
- Author
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Kristin D. Kernohan, Laure Frésard, Zachary Zappala, Taila Hartley, Kevin S. Smith, Justin Wagner, Hongbin Xu, Arran McBride, Pierre R. Bourque, CareRare Canada Consortium, Steffany A. L. Bennett, David A. Dyment, Kym M. Boycott, Stephen B. Montgomery, and Jodi Warman Chardon
- Subjects
0301 basic medicine ,Mutation ,In silico ,RNA ,Spinal muscular atrophy ,Biology ,medicine.disease ,medicine.disease_cause ,Bioinformatics ,DNA sequencing ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Spinal muscular atrophy with progressive myoclonic epilepsy ,RNA splicing ,Genetics ,ASAH1 ,medicine ,Genetics (clinical) - Abstract
At least 15% of the disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in noncoding regions. Whole-transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease-relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p C;p.Lys168Asn) and provided a molecular diagnosis of autosomal-recessive spinal muscular atrophy with progressive myoclonic epilepsy. Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for nonhematological conditions, providing a diagnosis for these otherwise unsolved patients.
- Published
- 2017
47. Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing
- Author
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Amanda C. Smith, Taila Hartley, Roberto Mendoza-Londono, J.S. Parboosingh, Bridget A. Fernandez, Jacek Majewski, Jeremy Schwartzentruber, Kym M. Boycott, Martine Tétreault, David A. Dyment, Chitra Prasad, Gabriella Horvath, Francois P. Bernier, Yanwei Xi, Asuri N. Prasad, Chandree L. Beaulieu, A.M. Innes, Christine M. Armour, C. A. Rupar, Eric Bareke, Lucie Dupuis, Ryan E. Lamont, Hugh J. McMillan, Tugce B. Balci, X.-R. Yang, and Julie Richer
- Subjects
Male ,0301 basic medicine ,Proband ,Canada ,Pediatrics ,medicine.medical_specialty ,Genotype ,Genetic counseling ,Consanguinity ,Bioinformatics ,03 medical and health sciences ,Exome Sequencing ,Genetics ,Humans ,Medicine ,Family ,Genetic Predisposition to Disease ,Genetic Testing ,Clinical phenotype ,Genetic Association Studies ,Genetics (clinical) ,Exome sequencing ,Retrospective Studies ,Disease gene ,business.industry ,Siblings ,Genetic Diseases, Inborn ,Pedigree ,3. Good health ,Multisystem disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,Mutation ,Dual diagnosis ,Female ,business - Abstract
Background Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. Aims We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. Materials & methods We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. Results Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. Conclusion Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
- Published
- 2017
48. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy
- Author
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Taila Hartley, Thi-Tuyet-Mai Nguyen, Jacek Majewski, Anik St-Denis, Philippe M. Campeau, David A. Dyment, Taroh Kinoshita, Françoise Le Deist, Devon L. Johnstone, Yoshiko Murakami, Asif Doja, Claire Goldsmith, Martine Tétreault, Justin D. Wagner, Kym M. Boycott, Kristin D. Kernohan, Dennis E. Bulman, and Lijia Huang
- Subjects
Adult ,0301 basic medicine ,Glycosylation ,Glycosylphosphatidylinositols ,Developmental Disabilities ,Protein subunit ,Hemoglobinuria, Paroxysmal ,Compound heterozygosity ,Immunoglobulin D ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Seizures ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Global developmental delay ,Child ,Molecular Biology ,Gene ,Genetics (clinical) ,biology ,Membrane Proteins ,General Medicine ,Phenotype ,Hypotonia ,Pedigree ,030104 developmental biology ,Hexosyltransferases ,chemistry ,Mutation ,biology.protein ,Muscle Hypotonia ,medicine.symptom ,Spasms, Infantile - Abstract
There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.
- Published
- 2017
49. Expansion of the <scp>GLE1</scp> ‐associated arthrogryposis multiplex congenita clinical spectrum
- Author
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Jillian S. Parboosingh, Kym M. Boycott, Carsten G. Bönnemann, A. Micheil Innes, Christopher Smith, Jean K. Mah, Francois P. Bernier, and Ryan E. Lamont
- Subjects
Male ,musculoskeletal diseases ,0301 basic medicine ,Nucleocytoplasmic Transport Proteins ,Neuromuscular disease ,Genotype ,RNA Splicing ,Population ,Biology ,Compound heterozygosity ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Child ,education ,Exome ,Finland ,Genetics (clinical) ,Arthrogryposis ,Gastrostomy ,education.field_of_study ,Arthrogryposis multiplex congenita ,Lethal congenital contracture syndrome ,Infant, Newborn ,Spinal muscular atrophy ,medicine.disease ,Pedigree ,3. Good health ,030104 developmental biology ,Mutation ,medicine.symptom - Abstract
Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein.
- Published
- 2017
50. Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly
- Author
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Jeremy Schwartzentruber, Jacek Majewski, Susan Blaser, Nicole Martin, David Chitayat, Yanwei Xi, Arran McBride, Kym M. Boycott, Kristin D. Kernohan, and David A. Dyment
- Subjects
0301 basic medicine ,Genetics ,Microcephaly ,Methyltransferase ,030102 biochemistry & molecular biology ,Arginine ,Lysine ,Brachydactyly ,Methylation ,Biology ,medicine.disease ,Null allele ,03 medical and health sciences ,030104 developmental biology ,Histone ,medicine ,biology.protein ,Genetics (clinical) - Abstract
Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition.
- Published
- 2016
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