Work

Recessive SMC5 Variants in a Family with Near-Tetraploidy/Mosaic Variegated Aneuploidy

Year: 2025

Type: article

Abstract: Background/Objectives: Mosaic variegated aneuploidy (MVA) is a rare chromosomal instability disorder. Biallelic variants in SMC5, a core component of the DNA repair machinery, cause Atelis Syndrome, characterized by severe growth failure and multi-system abnormalities. This study aimed to identify the genetic cause in a patient with MVA and a distinct, milder phenotype. Methods: We conducted comprehensive clinical and cytogenetic assessments, chromosomal karyotyping, and trio-based exome sequencing on a proband with hypospadias and chromosomal instability. Identified variants were validated by Sanger sequencing and assessed for pathogenicity using ACMG/AMP guidelines. Results: Cytogenetic analysis revealed near-tetraploidy (9.7%) and MVA (46.9%). Exome sequencing identified novel compound heterozygous SMC5 variants, a nonsense c.2221G>T (p.Glu741Ter) and a missense c.3065A>G (p.Asn1022Ser), both predicted to disrupt SMC5/6 complex function. The proband presented with hypospadias and mild developmental delay but lacked the severe neurological, cardiac, or hematological manifestations typical of Atelis Syndrome. Karyotype analysis showed a distinct pattern of chromosomal abnormalities, including a high frequency of marker chromosomes. Conclusions: This report expands the genotypic and phenotypic spectrum of SMC5-related disorders, confirming its association with MVA/near-tetraploidy and describing a novel attenuated clinical presentation. The findings highlight distinct cytogenetic patterns potentially differentiating DNA repair-defective MVA from other subtypes.

Source: Diagnostics

DOI: 10.3390/diagnostics15233022