Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder

Abstract

It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations—single nucleotide variants (SNVs) or small insertions and deletions (indels)—with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings’ shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.

Inherited unbalanced translocation (4p16.3p15.32 duplication/8p23.3p23.2deletion) in the four generation pedigree with intellectual disability/developmental delay

“…He carried a de novo unbalanced translocation [der(8)t(4;8) (p16.1 → pter; 23.1 → pter)] detected by SNP microarray. Two siblings were identified as having ID and ASD [22]. In our study, no dysmorphism were detected in the patient except for DD/ID, and there were not severe clinical symptoms, such as ASD, repetitive behavior or obsessive compulsive disorder.…”

“…Few cases of unbalanced translocation with both chromosome 4 short arm terminal duplication and chromosome 8 short arm terminal deletion have been reported. The recently published literature is summarized in Table 2 [20][21][22]. A 5-month-old baby with facial deformity, heart defect, and abnormal genitourinary system was too young to exhibit developmental abnormalities [20].…”

FAM193A is a positive regulator of p53 activity

“…Encoded by a gene in the Huntington’s disease locus, very little is known about the molecular function of the FAM193A protein. The few published studies primarily link FAM193A to neurological disorders such as Wolf-Hirschhorn syndrome 76 or autism 77 and to cancer-related osteonecrosis of the jaw and osteoporosis. 78 A region within 200 bp of a transcription start site for FAM193A was found to be hypomethylated in the dorsolateral prefrontal cortex in humans compared with chimpanzees and macaques.…”