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

Detelina Grozeva,Mark Corbett,Kathryn Friend,Jamie Bentham,Catherine Cosgrove,Michael Field,Keren Carss,Shoumo Bhattacharya,Marie Shaw,Bernard Keavney,Elizabeth Thompson,Anna Hackett,Matthew Hurles,F Lucy Raymond,Alessandra Renieri,Eric Haan,Olivera Spasić-Bošković ,J Alaina Floyd ,María-Isabel Tejada ,Jozef Gécz ,Zaamin B Hussain ,Roger E Stevenson ,Charles E Schwartz

doi:10.1002/humu.22901

Abstract

ABSTRACTTo 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.

Highlights

As the quality of antenatal and postnatal care improves, the genetic contribution to intellectual disability (ID) becomes ever more significant and has emerged as the commonest phenotypic manifestation of a constitutional genomic abnormality [Ropers, 2010]
These individuals were excluded from the subsequent analysis, as they were outliers from the variant distribution and the variants were likely to be due to technical artifacts
In order to estimate the sensitivity with which we have identified causative LoF variants, and to gain additional insights into disease etiology, we assessed the enrichment of LoF variants in sequenced ID-associated genes in our cohort, compared with a comparison dataset, using the cohort allelic sums test (CAST)

Summary

Introduction

As the quality of antenatal and postnatal care improves, the genetic contribution to intellectual disability (ID) becomes ever more significant and has emerged as the commonest phenotypic manifestation of a constitutional genomic abnormality [Ropers, 2010]. Strategies to identify novel disease causing genes have successfully used de novo trio analysis to compare the proband’s genome against the parental genomes with a diagnostic rate of 15%–40% [de Ligt et al, 2012; Rauch et al, 2012; Gilissen et al, 2014; Hamdan et al, 2014; The Deciphering Developmental Disorders Study, 2014] and a further 10%–20% diagnostic rate using a homozygosity mapping or biallelic variant analysis strategy [Musante and Ropers, 2014]. Analysis of singletons allows detection of novel genes by analysis of a large number of cases in a replication cohort. This strategy has been successfully used to identify novel ID-associated genes where multiple independent loss-of-function (LoF) variants cause disease (e.g., SETD5; MIM #615743) [Grozeva et al, 2014], the interpretation of rare missense variants is challenging and uncertain

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Conclusion