Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a group of clinically and genetically heterogeneous neurodevelopmental disorders. Recent tremendous advances in the whole exome sequencing (WES) enable rapid identification of variants associated with ASD including single nucleotide variations (SNVs) and indels. To further explore genetic etiology of ASD in Chinese children with negative findings of copy number variants (CNVs), we applied WES in 80 simplex families with a single affected offspring with ASD or suspected ASD, and validated variations predicted to be damaging by Sanger sequencing. The results showed that an overall diagnostic yield of 8.8% (9.2% in the group of ASD and 6.7% in the group of suspected ASD) was observed in our cohort. Among patients with diagnosed ASD, developmental delay or intellectual disability (DD/ID) was the most common comorbidity with a diagnostic yield of 13.3%, followed by seizures (50.0%) and craniofacial anomalies (40.0%). All of identified de novo SNVs and indels among patients with ASD were loss of function (LOF) variations and were slightly more frequent among female (male vs. female: 7.3% vs. 8.5%). A total of seven presumed causative genes (CHD8, AFF2, ADNP, POGZ, SHANK3, IL1RAPL1, and PTEN) were identified in this study. In conclusion, WES is an efficient diagnostic tool for diagnosed ASD especially those with negative findings of CNVs and other neurological disorders in clinical practice, enabling early identification of disease related genes and contributing to precision and personalized medicine.

A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination

“…Individual data points are superimposed onto means ± SEM. n = 15 +/+ males, 14 +/+ females, 8 +/− males (5 m+/p−, 3 m−/p+), and 12 +/− females (10 m+/p−, 2 m−/p+) social novelty [Katayama et al, 2016;Platt et al, 2017], whereas other groups reported no changes in this phase of the three-chamber test [Gompers et al, 2017;Jung et al, 2018]. Our Chd8 mutant mice perform statistically the same as wild-type in both the sociability (Figure 2 .…”

“…A commonly used assay to test for social deficits in mice is the three-chamber test for sociability and social novelty [Crawley, 2004]. Previous characterizations of Chd8 mutant mice revealed no deficits in sociability on this assay [Gompers et al, 2017;Jung et al, 2018;Katayama et al, 2016;Platt et al, 2017;Suetterlin et al, 2018]. Some groups reported a deficit in recognizing Figure 1.…”

“…The gene structure of Chd8, the location of mutations in mouse models previously generated in the literature [Gompers et al, 2017;Jung et al, 2018;Katayama et al, 2016;Platt et al, 2017 ;Suetterlin et al, 2018], and the targeting vector used for the current study are depicted in Figure 1(a). Consistent with previously published lines, homozygous mutants were embryonic lethal, but heterozygous mutants, which are haploinsufficient for the full-length protein (Figure 1(b)) were used for subsequent behavioral phenotyping.…”

“…Self-grooming is often elevated in mouse models of ASD and is thought to represent a repetitive behavior [Lewis, Tanimura, Lee, & Bodfish, 2007]. However, most lines of Chd8 mutant mice are no different than wild-type mice on self-grooming assays [Gompers et al, 2017;Katayama et al, 2016;Platt et al, 2017;Suetterlin et al, 2018]. One line of Chd8 mutant mice has elevated rates of selfgrooming, but only under certain conditions: it only occurs after prolonged social isolation and it only occurs in male mice [Jung et al, 2018].…”

Phenotypic expansion of POGZ‐related intellectual disability syndrome (White‐Sutton syndrome)

“…To date, over 50 cases have been reported in the literature (Dentici et al, ; Du et al, ; Fromer et al, ; Fukai et al, ; Gilissen et al, ; Gulsuner et al, ; Hashimoto et al, ; Homsy et al, ; Iossifov et al, ; Longoni et al, ; Matsumura et al, ; Neale et al, ; Stessman et al, ; White et al, ; Yavarna et al, ; Ye et al, ). Here we report insights from an allelic series of 21 distinct POGZ variants in 22 individuals with WHSUS.…”