Whole Exome Sequencing Reveals Mutations in Known Retinal Disease Genes in 33 out of 68 Israeli Families with Inherited Retinopathies

AbstractRetinopathy of prematurity (ROP) is a vasoproliferative retinal disease affecting premature infants. In addition to prematurity itself and oxygen treatment, genetic factors have been suggested to predispose to ROP. We aimed to identify potentially pathogenic genes and biological pathways associated with ROP by analyzing variants from whole exome sequencing (WES) data of premature infants. As part of a multicenter ROP cohort study, 100 non-Hispanic Caucasian preterm infants enriched in phenotypic extremes were subjected to WES. Gene-based testing was done on coding nonsynonymous variants. Genes showing enrichment of qualifying variants in severe ROP compared to mild or no ROP from gene-based tests with adjustment for gestational age and birth weight were selected for gene set enrichment analysis (GSEA). Mean BW of included infants with pre-plus, type-1 or type 2 ROP including aggressive posterior ROP (n = 58) and mild or no ROP (n = 42) were 744 g and 995 g, respectively. No single genes reached genome-wide significance that could account for a severe phenotype. GSEA identified two significantly associated pathways (smooth endoplasmic reticulum and vitamin C metabolism) after correction for multiple tests. WES of premature infants revealed potential pathways that may be important in the pathogenesis of ROP and in further genetic studies.

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Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

Journal of Dental Research ◽

10.1177/0022034517724149 ◽

2017 ◽

Vol 97 (1) ◽

pp. 49-59 ◽

Cited By ~ 16

Author(s):

N. Dinckan ◽

R. Du ◽

L.E. Petty ◽

Z. Coban-Akdemir ◽

S.N. Jhangiani ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Permanent Teeth ◽

Tooth Agenesis ◽

Disease Genes ◽

Nonsense Mediated Decay ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variants ◽

Complex Inheritance

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

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759 – Significant Variants in Monogenic Inflammatory Bowel Disease Genes Identified by Whole Exome Sequencing of 400 Paediatric Patients

Gastroenterology ◽

10.1016/s0016-5085(19)37187-2 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-157-S-158

Author(s):

James J. Ashton ◽

Enrico Mossotto ◽

Imogen Stafford ◽

Tracy Coelho ◽

Nadeem A. Afzal ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Disease Genes ◽

Paediatric Patients ◽

Whole Exome ◽

Inflammatory Bowel

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Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes

Genome Biology ◽

10.1186/s13059-017-1174-6 ◽

2017 ◽

Vol 18 (1) ◽

Cited By ~ 39

Author(s):

Hongsheng Gui ◽

Duco Schriemer ◽

William W. Cheng ◽

Rajendra K. Chauhan ◽

Guillermo Antiňolo ◽

...

Keyword(s):

Functional Analysis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hirschsprung Disease ◽

Disease Genes ◽

Whole Exome

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O1-09-02: Whole Exome Sequencing of Late Onset Multiplex Families Identifies Rare Coding Variants in Known and Novel Alzheimer’s Disease Genes

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.342 ◽

2016 ◽

Vol 12 ◽

pp. P196-P197

Author(s):

Holly N. Cukier ◽

Brian W. Kunkle ◽

Sophie Rolati ◽

Patrice L. Whitehead ◽

Jeffery M. Vance ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Late Onset ◽

Disease Genes ◽

Whole Exome ◽

Multiplex Families ◽

Coding Variants

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B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.95 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S11

Author(s):

L Gauquelin ◽

T Hartley ◽

M Tarnopolsky ◽

DA Dyment ◽

B Brais ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Genetic Diseases ◽

Genetic Diagnosis ◽

Cerebellar Atrophy ◽

Clinical Findings ◽

Disease Genes ◽

Pathogenic Variants ◽

Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

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Revisiting disease genes based on whole-exome sequencing in consanguineous populations

Human Genetics ◽

10.1007/s00439-015-1580-3 ◽

2015 ◽

Vol 134 (9) ◽

pp. 1029-1034 ◽

Cited By ~ 7

Author(s):

Ahmed Shamia ◽

Ranad Shaheen ◽

Nouran Sabbagh ◽

Agaadir Almoisheer ◽

Anason Halees ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Genes ◽

Whole Exome

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Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi−Bickel Syndrome

Frontiers in Genetics ◽

10.3389/fgene.2020.601566 ◽

2021 ◽

Vol 11 ◽

Author(s):

Maryam Eghbali ◽

Kiyana Sadat Fatemi ◽

Shadab Salehpour ◽

Maryam Abiri ◽

Hassan Saei ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Glycogen Storage Disease Type ◽

Glycogen Storage ◽

Disease Genes ◽

Carrier Status ◽

Mendelian Disease ◽

Pathogenic Variants ◽

Glycogen Storage Diseases ◽

Whole Exome

Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG’s list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG’s list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.

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