Abstract
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.
Highlights
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases
Autism spectrum disorders (ASD) are highly genetic disorders, and current estimates indicate that there could be over 1,000 genes that contribute to ASD risk [1]
Very few genes are likely to contribute to more than 1% of ASD, and mutations of FMR1 and MECP2, considered among the most common causes of ASD, explain 2% and 0.5% of ASD, respectively
Summary
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. 22q13.3 deletions and mutations that lead to a loss of a functional copy of SHANK3 cause Phelan-McDermid syndrome, characterized by moderate to profound intellectual disability, severely delayed or absent speech, hypotonia, and ASD or ASD traits [2,3]. Because of its nonspecific clinical presentation, the diagnosis requires molecular genetic testing to identify SHANK3 deletions (the preferred method being chromosome microarray analysis) or mutations.
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