Heterogeneous Inheritance in Autism Genes Shared Across Neurodevelopmental and Neuromuscular Disorders in Consanguineous Singlets

Abstract Background Autosomal recessive genetic disorders are leading health concerns in countries with consanguineous marriage. However, previously there was no strong association of consanguinity with autosomal dominant or X-linked inheritance patterns. Whether this would be the case in singlet consanguineous families remained unexplored. Methods The current study aimed to identify the disease genes and their inheritance patterns in 12 independent Iranian consanguineous singlet families with syndromic autism. Results Exome sequencing revealed two missense and two nonsense variants (one in each gene: IQSEC2, FOXG1, DMD, and CHKB) in four out of 12 families, thereby offering an aetiologic diagnosis. Autism, intellectual disability, learning disability, developmental delay, and behavioral problems were common features in these four families, and three individuals presented with impaired motor skills such as abnormal gait. Muscular dystrophy coupled with hypotonia were noted in two individuals, whereas in the remaining two families ADHD combined with language/speech delay were present. Along with the two X-linked (IQSEC2 and DMD), one autosomal dominant (FOXG1) and one autosomal recessive genes (CHKB) were found in these four consanguineous families. Two genes-DMD and CHKB- are known to be mainly involved in muscular dystrophy. Limitation: our study significance is limited by the small sample size, 12 individuals, and lack of functional experiment on a VUS on the DMD variant. Conclusion Our findings illustrate the mixed inheritance pattern in consanguineous singlet families and highlight the association of autism spectrum disorder with muscular dystrophy, both of which are seemingly not related.