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.
Background:
Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by locus heterogeneity and variable expressivity. Patients suffering from WMS are described by short stature, brachydactyly, joint stiffness, congenital heart defects, and eye abnormalities. This disorder is inherited in two different modes; the autosomal dominant form of the disease occurs due to a mutation in
FBN1
, and the recessive form results from mutations in
ADAMTS10
,
ADAMTS17
, or
LTP2
genes.
Materials and Methods:
The family recruited in this study was a consanguineous Iranian family with an intellectually disabled girl referred to the Sadra Genetics laboratory, Shahrekord, Iran. The clinical history of family members was investigated. Whole-Exome Sequencing (WES) for the proband was performed. Sanger sequencing was used to assess the segregation of candidate variants in the other family members.
Results:
Whole-exome sequencing analysis revealed a novel heterozygote mutation in the proband located at the third TGF-β-binding protein-like (TB) domain of the
FBN1 g
ene (NM000138: c.2066A>G: (p. Glu689Gly), NP_000129.3, in exon 17 of the gene). Co-segregation analysis with Sanger sequencing confirmed this mutation in the affected members of the pedigree.
Conclusion:
Our findings represent an autosomal dominant form of specific WMS resulting from a substitution mutation in the
FBN1 g
ene. In addition to the typical manifestations of the disorder, mild intellectual disability (ID) was identified in the 8-year-old proband. Given the fact that ID is primarily reported in
ADAMTS10
mutated cases, this family was clinically and genetically a novel case.
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