3q27.1 deletion

The reported cases of 3q26.33q22.7 deletions share a distinct phenotype, which includes intrauterine growth restriction (IUGR), intellectual disability (ID), microcephaly, feeding difficulties, hypotonia, post-natal short stature, facial dysmorphisms, thrombocytopenia and dental anomalies. Previously, a 1.2Mb smallest region of overlap (SRO) was identified including 46 protein-coding genes. The authors add 7 new cases (2 of their own patients and 5 from other databases). All individuals underwent single nucleotide polymorphism microarray or array-based comparative genomic hybridization. These individuals revealed new features of the proposed deletion syndrome, including a bicuspid aortic valve, atrial septal defect, congenital malformation of the mesentery, and metopic craniosynostosis. Examination of the new individuals also confirmed more universal phenotypes arising from this region (IUGR, microcephaly, ID, developmental disability, distinctive facial features, post-natal growth restriction, hypotonia, neonatal feeding problems, and dental anomalies). Thrombocytopenia was observed in both a new case and previously reported cases. Through genetic analysis of the expanded cohort, Gear et al. were able to narrow the SRO from 1.2Mb to 430kb at 3q27.1, containing 20 protein-coding genes. The authors assert that the region is likely pathogenic in nature. Of the 20 genes within this region, 3 are predicted to be highly intolerant of loss of function: PMSD2, EIF4G1, and AP2M1. AP2M1 is proposed as a candidate for the neurodevelopmental characteristics in this deletion syndrome. Downregulating its expression in murine models causes a reduction in dendritic branching in cortical neurons, interfering with proper neural development. One of the patients in the authors’ practice had a point mutation in the AP2M1 gene. This individual had normal height and weight, lower IQ, autistic features, and seizures (Lennox-Gaustaut Syndrome), but no other manifestations of a 3q27.1 deletion. These facts support the proposal that the AP2M1 gene may be responsible for neurodevelopmental manifestations of this syndrome. The present study provides additional support for the involvement of THPO and CHRD in thrombocytopenia and cardiac anomalies, respectively. Gear et al. expanded the deletion cohort, allowing the researchers to confirm and build upon previously described features that support the existence of a 3q27.1 deletion syndrome, refine the SRO, and explore the role of AP2M1 in neurodevelopment.

Gear et al. “AP2M1 is a candidate gene for microcephaly and intellectual disability in 3q27.1 deletions”. “American Journal of Medical Genetics Part A” 2025, Advance online publication.