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

Area of Science:

• Genetics
• Human Molecular Genetics
• Clinical Genetics

Background:

• Deletions in the 3q26.33q27.2 chromosomal region are associated with a specific phenotype, but cases are rare.
• Understanding the genetic basis of these deletions is crucial for diagnosing and managing affected individuals.

Purpose of the Study:

• To characterize the phenotype associated with de novo 3q27 deletions.
• To identify the critical region and candidate genes responsible for the observed clinical features.
• To investigate the role of the AP2M1 gene in neurodevelopmental outcomes.

Main Methods:

• Analysis of seven new cases with de novo 3q27 deletions (under 5 Mb).
• Literature review and data compilation from 12 previously reported cases.
• Genomic analysis to narrow down the smallest region of overlap (SRO).
• Functional assessment of AP2M1 based on predicted intolerance to haploinsufficiency and murine models.

Main Results:

• A cohort of 19 individuals with 3q27 deletions showed common features: intrauterine growth restriction, intellectual disability, microcephaly, hypotonia, short stature, and facial dysmorphisms.
• Newly identified features include bicuspid aortic valve, atrial septal defect, mesenteric malformation, and metopic craniosynostosis.
• The SRO was narrowed to a 430 kb region at 3q27.1, containing 20 protein-coding genes.
• AP2M1 is proposed as a key gene, supported by a case with a de novo loss-of-function variant causing severe epilepsy.

Conclusions:

• 3q27 microdeletions result in a spectrum of neurodevelopmental and congenital anomalies.
• AP2M1 is a strong candidate gene for the neurodevelopmental phenotype, including epilepsy, associated with these deletions.
• This study refines the critical region and highlights AP2M1's significance in the clinical presentation of 3q27 deletions.