ABSTRACT
Loss-of-function variants in the dystrophin gene, a well-known cause of muscular dystrophies, have emerged as a mutational risk mechanism for autism spectrum disorder (ASD), which in turn is a highly prevalent (~ 1%) genetically heterogeneous neurodevelopmental disorder. Although the association of intellectual disability with the dystrophinopathies Duchenne (DMD) and Becker muscular dystrophy (BMD) has been long established, their association with ASD is more recent, and the dystrophin genotype-ASD phenotype correlation is unclear. We therefore present a review of the literature focused on the ASD prevalence among dystrophinopathies, the relevance of the dystrophin isoforms, and most particularly the relevance of the genetic background to the etiology of ASD in these patients. Four families with ASD-DMD/BMD patients are also reported here for the first time. These include a single ASD individual, ASD-discordant and ASD-concordant monozygotic twins, and non-identical ASD triplets. Notably, two unrelated individuals, which were first ascertained because of the ASD phenotype at ages 15 and 5 years respectively, present rare dystrophin variants still poorly characterized, suggesting that some dystrophin variants may compromise the brain more prominently. Whole exome sequencing in these ASD-DMD/BMD individuals together with the literature suggest, although based on preliminary data, a complex and heterogeneous genetic architecture underlying ASD in dystrophinopathies, that include rare variants of large and medium effect. The need for the establishment of a consortia for genomic investigation of ASD-DMD/BMD patients, which may shed light on the genetic architecture of ASD, is discussed.
ABSTRACT
Prediction of pathogenicity of rare copy number variations (CNVs), a genomic alteration known to contribute to the etiology of autism spectrum disorder (ASD), represents a serious limitation to interpreting genetic tests, particularly for genetic counseling purposes. Chromosomal microarray analysis (CMA) was conducted in a unique collection of 144 Brazilian individuals with ASD of strong European and African ancestries. Rare CNVs were detected in 39 patients: 41 of unknown significance (VUS), four pathogenic and one likely pathogenic CNVs (clinical yield of 4.1%; 5/122). Based on gene content and recurrence in three large cohorts [a Brazilian neurodevelopmental disorder cohort, the autism MSSNG cohort, and the Canadian-based Centre for Applied Genomics microarray database], this work strengthened the pathogenicity of 14 genes (FAT1, CAMK4, BIRC6, DPP6, CSMD1, CTNNA3, CDH8/CDH11, CDH13, OR1C1, CNTN6, CNTNAP4, FGF2 and PTPRN2) within 14 CNVs. Notably, enrichment of cell adhesion proteins to ASD etiology was identified (p < 0.05), highlighting the importance of these gene families in the etiology of ASD.
