Dystrophin genetic variants and autism

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.

Fig. 1

Schematic representation of DMD exons gene and main protein isoforms. a Representation of the 79 exons of the dystrophin gene. Exons’ format represents whether splicing between adjacent exons maintain the protein’s ORF (open read frame) or create out of frame, truncated, proteins. A black arrow indicates the initiation of the main isoforms. The longest isoforms, Dp427m, Dp427p and Dp427c, differ only for their first exon and are named according to their principal site of expression. In addition, four internal promoters, found in different introns of the larger isoforms, control the expression of the smaller isoforms Dp260, Dp140, Dp116, and Dp71/Dp40, named after their molecular weight. DMD variants here described are represented (written in red): three SNVs affecting exons 2 (family 3), 14 (family 4), 78 (family 2) and a 2–9 exons deletion (family 1). Exons’ colors represent the full-length isoform main domains of the dystrophin protein (which is shown in b orange = N-terminus (which contains the actin-binding domain); grey = hinge domains; green = ROD domain, composed of 24 spectrin-like domains; yellow = the cysteine rich domain; and dark blue = C-terminus portion. b Representation of the dystrophin isoforms with their domains and the main tissue that they are expressed in. In addition to the ones represented, alternative splicing patterns and polyadenylation sites create a greater number of dystrophin isoforms, increasing its complexity. The smallest isoform, Dp40, shares the Dp71 promoter region, but differs by its truncated 3′ portion