Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

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Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Kidney International ◽

10.1038/ki.2015.317 ◽

2016 ◽

Vol 89 (2) ◽

pp. 468-475 ◽

Cited By ~ 41

Author(s):

Daniela A. Braun ◽

Markus Schueler ◽

Jan Halbritter ◽

Heon Yung Gee ◽

Jonathan D. Porath ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Childhood Onset ◽

Familial Cases ◽

Whole Exome

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Racial and Ethnic Disparities in Genetic Testing for Hearing Loss: a Systematic Review and Synthesis

10.21203/rs.3.rs-484764/v1 ◽

2021 ◽

Author(s):

Stephanie L Rouse ◽

Michelle M Florentine ◽

Emily Taketa ◽

Dylan K Chan

Keyword(s):

Hearing Loss ◽

Native American ◽

Genetic Testing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Single Gene ◽

Ethnic Disparities ◽

Multiple Gene ◽

Whole Exome ◽

Racial Ethnic

Abstract Racial/ethnic disparities in the diagnostic efficacy of genetic testing for hearing loss has been described. These disparities may relate to differences in variant classification between different racial/ethnic groups, which may in turn derive from disparate representation of these groups in the published literature. We sought to quantify racial/ethnic disparities in the published literature on the human genetics of hearing loss. We conducted a search of PubMed for articles describing single-gene, multiple-gene, or whole-exome sequencing for individuals with sensorineural hearing loss. Data on the populations studied, including race/ethnicity and/or region of origin, subjects tested, and method of testing, were extracted. 1,355 unique populations representing 311,092 subjects from 1,165 studies were included. Overall, White and Asian populations and subjects were equivalently represented, but Latinx, Black, and Native American/Hawaiian groups were significantly underrepresented; over 96% of all subjects in the published literature were White or Asian. Within racial/ethnic groups, the majority of subjects derived from a small subset of countries. The observed racial/ethnic disparity was greater for multiple-gene and whole-exome sequencing than for single-gene sequencing. These findings illustrate the large disparity in published literature on the genetics of hearing loss, and demonstrate the need for increased representation of Latinx, Black, and Native American populations.

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Whole‐exome sequencing suggests multiallelic inheritance for childhood‐onset Ménière's disease

Annals of Human Genetics ◽

10.1111/ahg.12327 ◽

2019 ◽

Vol 83 (6) ◽

pp. 389-396 ◽

Cited By ~ 2

Author(s):

Sini Skarp ◽

Laura Kanervo ◽

Jouko Kotimäki ◽

Martti Sorri ◽

Minna Männikkö ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Meniere’S Disease ◽

Menière’S Disease ◽

Meniere's Disease ◽

Ménière’S Disease ◽

Menière's Disease ◽

Childhood Onset ◽

Whole Exome ◽

Ménière's Disease

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Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.002969 ◽

2020 ◽

Vol 13 (5) ◽

pp. 504-514

Author(s):

Zuhair N. Al-Hassnan ◽

Abdulrahman Almesned ◽

Sahar Tulbah ◽

Ali Alakhfash ◽

Faten Alhadeq ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genome Sequencing ◽

Founder Mutation ◽

Genetic Test ◽

Whole Genome ◽

Childhood Onset ◽

Whole Exome ◽

The Impact

Background: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. Methods: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. Results: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1 ). Conclusions: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

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Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Journal of Experimental Medicine ◽

10.1084/jem.20101597 ◽

2010 ◽

Vol 207 (11) ◽

pp. 2307-2312 ◽

Cited By ~ 215

Author(s):

Minji Byun ◽

Avinash Abhyankar ◽

Virginie Lelarge ◽

Sabine Plancoulaine ◽

Ayse Palanduz ◽

...

Keyword(s):

T Cell ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Single Gene ◽

Human Herpesvirus ◽

Kaposi Sarcoma ◽

Single Family ◽

Inborn Errors ◽

Whole Exome ◽

Classic Kaposi Sarcoma

Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.

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Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

10.1101/525683 ◽

2019 ◽

Author(s):

◽

Yen-Chen Anne Feng ◽

Daniel P. Howrigan ◽

Liam E. Abbott ◽

Katherine Tashman ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Focal Epilepsy ◽

Single Gene ◽

European Ancestry ◽

Whole Exome ◽

Genes Encoding ◽

Rare Genetic Variation ◽

Generalized Epilepsy

AbstractSequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

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