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

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.