Dataset Information

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

ABSTRACT: To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ?11% of the cases (113 variants in 107/986 individuals: ?8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ?3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.

SUBMITTER: Grozeva D

PROVIDER: S-EPMC4833192 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

Grozeva Detelina D Carss Keren K Spasic-Boskovic Olivera O Tejada Maria-Isabel MI Gecz Jozef J Shaw Marie M Corbett Mark M Haan Eric E Thompson Elizabeth E Friend Kathryn K Hussain Zaamin Z Hackett Anna A Field Michael M Renieri Alessandra A Stevenson Roger R Schwartz Charles C Floyd James A B JA Bentham Jamie J Cosgrove Catherine C Keavney Bernard B Bhattacharya Shoumo S Hurles Matthew M Raymond F Lucy FL

Human mutation 20150930 12

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP ...[more]

PMID: 26350204

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Project description:Background: Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID. Objective: The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID. Methods: Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing. Results: Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of ZDHHC9 or autosomal dominant inheritance of SMARCB1, CHD8, LAMA5, NSD1, PAX6, CACNA1H, MBD5, FOXP1, or KCNK18 mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be de novo mutation present in the proband only. A total of seven may be de novo mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except LAMA5. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID. Conclusion: Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be de novo, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.

Dataset Information

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

Publications

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

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