Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data

Abstract

SummaryBackgroundHuman genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount.MethodsThe Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team.FindingsAround 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation.InterpretationImplementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene–phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial.FundingHealth Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

“…For the seven individuals identified via the DDD study, trio‐based exome sequencing was performed on the affected individual and their parents, as previously described [Wright et al, 2014]. Each affected individual has also had a high‐resolution analysis for copy number abnormalities using array‐based comparative genomic hybridization (aCGH).…”

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

“…In six cases, the KANSL1 variant was identified using whole-exome sequencing (cases 35,38,39,41,42,44), two of which originated from the Deciphering Developmental Disorders (DDD) project (www.ddduk.org/). 33 One variant (case 40) was identified using a molecular inversion probes (MIP) assay. 34 Other patients underwent direct sequencing of KANSL1 owing to clinical evidence of KdVS phenotype.…”

“…In the first 1133 children with developmental disorders in the DDD project (www.ddduk.org/), one de novo KANSL1 variant was identified, giving a frequency of 0.09%. 33 Coe et al 34 report on 7 KANSL1 SNVs among 4716 cases with unexplained developmental delay or autism resulting in a frequency of 0.15% (although at least one of the mutations was inherited from a non-affected mother, see the section 'Genetic testing'). These data suggest that the pathogenic KANSL1 SNVs might be as frequent as the deletion, but more studies are needed to determine an unbiased prevalence of the syndrome.…”

Genetics in the 21st Century: Implications for patients, consumers and citizens

“…In 2014, the Deciphering Developmental Disorders Study reported the first results from the sequencing of 12,000 children with developmental disorders 2 . At the same time, work began on a project to sequence 100,000 genomes of 70,000 NHS patients 3 .…”