AP2M1 Is a Candidate Gene for Microcephaly and Intellectual Disability in 3q27.1 Deletions

Deletions of the 3q26.33q27.2 region appear to correlate with a distinct phenotype, although there are few reported cases. Here, we present seven previously unreported individuals carrying de novo 3q27 deletions (under 5 Mb), which include the AP2M1 (adaptor-related protein complex 2, mu-1 subunit) gene and summarize data from 12 previously reported cases from the literature. The overall cohort of 19 individuals demonstrates almost universal intrauterine growth restriction, intellectual disability, and post-natal microcephaly, along with common features of hypotonia, post-natal short stature, and facial dysmorphisms. Newly identified features include bicuspid aortic valve, atrial septal defect, congenital malformation of the mesentery, and metopic craniosynostosis, present in a subset of individuals. These seven newly identified individuals allow narrowing of the previously reported smallest region of overlap to 430 kb at 3q27.1. This region includes 20 protein coding genes. We propose AP2M1 as the most likely contributor to the neurodevelopmental phenotype, based on its predicted intolerance to haploinsufficiency, functional evidence in murine models, and similar phenotypes associated with other adaptor-protein-complex-family members. Furthermore, we report the first individual with a de novo loss-of-function nonsense single nucleotide variant in AP2M1 with neurodevelopmental features including severe epilepsy. We discuss the implications of this finding in the context of previously reported epileptic encephalopathy in individuals with the recurrent p.Arg170Trp variant in AP2M1. In conclusion, our study expands the phenotypic spectrum of 3q27 microdeletions and highlights the potential importance of AP2M1 in its clinical presentation.