Genomic diagnosis for children with intellectual disability and/or developmental delay

Abstract

BackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.MethodsWhole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected).ResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP.ConclusionsOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0433-1) contains supplementary material, which is available to authorized users.

Systematic reanalysis of genomic data improves quality of variant interpretation

“…None of the variants in this table were returned to probands at time of the first analysis, nor was ACMG scoring or criteria explicitly used at that time. ‡ Note that this variant was previously reported with our initial study findings 8 , although the variant was recently found in one additional unrelated proband in our study, represented here. § ACMG scoring criteria do not apply to UPD. …”

“…An initial reanalysis effort was described in an analysis of the first 371 affected probands 8 , but an expanded and improved reanalysis pipeline, including new findings, approaches, and implications, is presented here.…”

NBEA: Developmental disease gene with early generalized epilepsy phenotypes

“…NBEA variants were identified in 22 previously unreported cases and two cases already reported in the literature 7 . All variants were confirmed to be de novo with the exception of individual 13.…”

“…It is not currently associated with disease in the Online Mendelian Inheritance in Man (OMIM) database but is a candidate gene for autism based on linkage studies and the identification of microdeletions and a reciprocal balanced translocation involving NBEA in patients with autism 2–6 . More recently, two de novo NBEA variants were identified through whole exome sequencing (WES) in large cohorts of patients with neurodevelopmental disease (NDD) phenotypes, implicating NBEA as a candidate gene 7 .…”

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

“…Table 1 summarizes the relevant clinical information, details about each variant, inheritance, number of genes tested, ACMG classification, and Online Mendelian Inheritance in Man disease entities related to specific genes. [19][20][21][22][23][24] The complete panel results for each patient, including genetic variants considered out of the scope of the present study, are available as Appendix S2.…”