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. 2017 May 30;9(1):43.
doi: 10.1186/s13073-017-0433-1.

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

Kevin M Bowling  1 , Michelle L Thompson  1 , Michelle D Amaral  1 , Candice R Finnila  1 , Susan M Hiatt  1 , Krysta L Engel  1 , J Nicholas Cochran  1 , Kyle B Brothers  2 , Kelly M East  1 , David E Gray  1 , Whitley V Kelley  1 , Neil E Lamb  1 , Edward J Lose  3 , Carla A Rich  2 , Shirley Simmons  3 , Jana S Whittle  1   4 , Benjamin T Weaver  1   3 , Amy S Nesmith  1 , Richard M Myers  1 , Gregory S Barsh  1 , E Martina Bebin  3 , Gregory M Cooper  5
Affiliations

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

Kevin M Bowling et al. Genome Med. .

Abstract

Background: Developmental 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.

Methods: Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected).

Results: Pathogenic 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.

Conclusions: Our 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.

Keywords: CSER; Clinical sequencing; De novo; Developmental delay; Intellectual disability.

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Figures

Fig. 1
Fig. 1
Intronic variants in ALG1 and MTOR disrupt splicing and introduce early stop codons. a Diagram showing the region of ALG1 surrounding the variant found in the proband and mother, an A > G transition three nucleotides downstream from the splicing donor site of intron 11. E = exon. b The ALG1 variant leads to increased retention of intron 11. cDNA from patient derived RNA extracted from blood was amplified using the PCR F/PCR R primer set (shown in panel 1A) to test for intron 11 retention. The control samples are cDNA derived from RNA extracted from blood of an unrelated individual as well as the father of the proband that did not harbor the variant. The proband, and mom, from which the variant was transmitted, both harbor the incorrectly spliced transcript retaining intron 11. Control reactions lacking RT were also performed and did not show the PCR product containing the fully retained intron (data not shown). c, d qPCR analysis shows that the variant leads to inclusion of the entire intron 11. Controls are two unrelated individuals and the father of the proband. The affected individuals are the proband and mother. e Diagram showing the region of MTOR surrounding the variant, an A > G transition two nucleotides upstream of the splicing acceptor site. E = exon. f The region surrounding intron 4 was amplified using PCR F and PCR R (position indicated in (e)), and shows partial retention of the intron. The retained partial intron was not detected in control reactions lacking RT (data not shown). g, h qPCR from blood RNA shows that the 5′ splice site is not affected by the variant, but that the 3′ acceptor site is, leading to partial retention (134 bp) of intron 4. Controls included unrelated individuals and the maternal half aunt of the proband. Affected individuals are the proband and half-sibling. For all qPCR analyses, RNA was extracted from blood and ΔΔCT values were calculated as a percent of affected individuals and normalized to GAPDH. The sequences of all oligos used are found in Additional file 3: Table S7
Fig. 2
Fig. 2
Ranks of pathogenic/likely pathogenic variants filtered without parental data relative to trio-defined de novo events. Most pathogenic/likely pathogenic variants, even under models that only consider population frequencies (e.g. “Rare”), rank (based on CADD) among the top 25 hits in a patient, and many rank as the top hit. Restrictions to rare coding variants and/or those affecting OMIM/DDG2P [13, 16] genes further enrich for causal variants among top candidates, making diagnosis feasible without parents
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