Whole-Exome Sequencing Identifies Three Candidate Homozygous Variants in a Consanguineous Iranian Family with Autism Spectrum Disorder and Skeletal Problems

Abstract

Autism spectrum disorder (ASD) is characterized by 3 core symptoms with impaired social communication, repetitive behavior, and/or restricted interests in early childhood. As a complex neurodevelopmental disorder (NDD), the phenotype and severity of autism are extremely heterogeneous. Genetic factors have a key role in the etiology of autism. In this study, we investigated an Azeri Turkish family with 2 ASD-affected individuals to identify probable ASD-causing variants. First, the affected individuals were karyotyped in order to exclude chromosomal abnormalities. Then, whole-exome sequencing was carried out in one affected sibling followed by cosegregation analysis for the candidate variants in the family. In addition, SNP genotyping was carried out in the patients to identify possible homozygosity regions. Both proband and sibling had a normal karyotype. We detected 3 possible causative variants in this family: c.5443G>A; p.Gly1815Ser, c.1027C>T; p.Arg343Trp, and c.382A>G; p.Lys128Glu, which are in the FBN1, TF, and PLOD2 genes, respectively. All of the variants cosegregated in the family, and SNP genotyping revealed that these 3 variants are located in the homozygosity regions. This family serves as an example of a multimodal polygenic risk for a complex developmental disorder. Of these 3 genes, confluence of the variants in FBN1 and PLOD2 may contribute to the autistic features of the patient in addition to skeletal problems. Our study highlights the genetic complexity and heterogeneity of NDDs such as autism. In other words, in some patients with ASD, multiple rare variants in different loci rather than a monogenic state may contribute to the development of phenotypes.

Shifting the Focus of Molecular Syndromology from Individual Diagnoses to Outcome Analyses

“…CNVs were found in 11.9% of the patients with multiple diagnoses. Molecular Syndromology has already published several case reports on "dual diagnoses" and welcomes in particular such reports combining in-depth, structured phenotyping with elucidation of multiple genomic variants by genome wide methods [Farajzadeh Valilou et al, 2020;Demir et al, 2022;Doğulu et al, 2022;Izumi et al, 2023, in this issue].…”