Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders (original) (raw)
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Human genetics, 2018
Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two famili...
2016
Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed ov...
Clinical genetics, 2017
Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnos...
2019
Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical exome sequencing (CES) has been shown to provide a high diagnostic yield for these disorders in the European population but remains to be demonstrated for the Indian population. Methods: A cohort of 19 idiopathic patients with neurological phenotypes, primarily intellectual disability and developmental delay, were recruited. CES covering 4620 genes was performed on all patients. Candidate variants were validated by Sanger sequencing. Results: CES in 19 patients provided identified 21 variants across 16 genes which have been associated with different neurological disorders. Fifteen variants were reported previously and 6 variants were novel to our study. Eleven patients were diagnosed with autosomal dominant de novo variants, 7 with autosomal recessive and 1 with X-linked recessive variants. CES provided definitive diagnosis to 10 patients, hence the diagnostic yield was 53%. Conclusion: Ou...
Exome sequencing identifies novel and known mutations in families with intellectual disability
BMC Medical Genomics
Background Intellectual disability (ID) is a phenotypically and genetically heterogeneous disorder. Methods In this study, genome wide SNP microarray and whole exome sequencing are used for the variant identification in eight Pakistani families with ID. Beside ID, most of the affected individuals had speech delay, facial dysmorphism and impaired cognitive abilities. Repetitive behavior was observed in MRID143, while seizures were reported in affected individuals belonging to MRID137 and MRID175. Results In two families (MRID137b and MRID175), we identified variants in the genes CCS and ELFN1, which have not previously been reported to cause ID. In four families, variants were identified in ARX, C5orf42, GNE and METTL4. A copy number variation (CNV) was identified in IL1RAPL1 gene in MRID165. Conclusion These findings expand the existing knowledge of variants and genes implicated in autosomal recessive and X linked ID.
Genomic diagnosis for children with intellectual disability and/or developmental delay
2016
ABSTRACTBackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.MethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).ResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15...
PurposeDespite significant progress in unravelling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis following microarray and/or exome sequencing. Here we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in NDD participants from the NIHR BioResource project.MethodsShort-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, complex SVs, or required distal variant phasing.ResultsCausal variants were identified in 36% affected individuals (177/489) and a further 26% (129/489) had a variant of uncertain significance, after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were SNVs/indels, and the remainder we...
Whole Exome Sequencing in Neurodevelopmental Disorders: A Single Center Study
Basic and Clinical Neuroscience Journal, 2024
Introduction: Neurodevelopmental disorders (NDDs) comprise clinically and genetically heterogeneous diseases. It is challenging to diagnose the underlying origin of NDDs. We aim to evaluate whole exome sequencing (WES) results in our NDD patients and the responsible genetic variants. Methods: This study evaluated the WES analysis of 25 NDD patients retrospectively. Also, the diagnostic yield of WES in our cases and clinical findings were examined. Results: After WES analysis, we diagnosed 13 patients (52%) with pathogenic and likely pathogenic variants, but 12(48%) had variants of uncertain significance (VUS). However, after phenotype consistency and following segregation analysis, we reevaluated 2 VUS as the disease-causing variants, and our yield rate increased to 60%. We also reported the secondary findings. Conclusion: Our study’s diagnostic yield of WES in NDD was 60%. The latest American College of Medical Genetics and Genomics (ACMG) guideline recommends WES as the first-tier test in NDD. WES is time- and cost-effective when performed on a well-selected patient. Also, determining the underlying cause of NDD will provide patients with a more precise diagnosis and clinical follow-up.