De Novo 3q27.1 Microdeletion Refines the Critical Region and Implicates PSMD2 Haploinsufficiency in Growth and...

Interstitial deletions involving 3q27.1 define a distinct microdeletion syndrome characterized by prenatal-onset growth restriction, postnatal microcephaly, hypotonia, intellectual disability, and distinctive craniofacial features. While AP2M1 haploinsufficiency has been proposed as the primary driver of this phenotype, the full spectrum of dosage-sensitive genes within the locus remains unclear. Here, we report a patient with a de novo heterozygous 3q27.1 microdeletion and delineate a refined minimal smallest region of overlap (SRO) of approximately 189 kb, representing the narrowest critical interval associated with the 3q27.1 microdeletion phenotype to date. Chromosomal microarray and exome-based CNV analysis confirmed the deletion, which encompasses PSMD2, EIF4G1, and POLR2H but excludes AP2M1 and DVL3. The patient exhibited severe intrauterine growth restriction, microcephaly, global developmental delay, and mild dysmorphism, consistent with the established 3q27.1 phenotype. PSMD2 encodes a non-ATPase regulatory subunit of the 26S proteasome, and its loss may disrupt proteasome-mediated protein turnover and neuronal homeostasis. Comparison with previously published cases and an overlapping ClinVar variant (ID: 60129) with similar features supports the pathogenicity of this minimal deletion. Our findings refine the 3q27.1 critical region, propose PSMD2 haploinsufficiency as a likely molecular mechanism underlying growth and neurodevelopmental defects. Further cases and functional studies are needed to confirm PSMD2 causality and clarify the proteasome-related mechanisms underlying 3q27.1 microdeletion syndrome.