Co-occurrence of homozygous ALMS1 variant, 17q11.2 mosaic and germline deletions, and VSX2 nonsense variant in a single family.

INTRODUCTION: : Alström syndrome (AS) is a rare, progressive disorder inherited in an autosomal recessive manner. It is characterized by multisystem involvement, including retinal dystrophy, hearing loss, obesity, insulin resistance, and cardiomyopathy. AS is typically associated with biallelic pathogenic variants in the ALMS1 gene. In this study, three distinct inherited disorders caused by different genetic mechanisms observed within the same family were evaluated together. OBJECTIVE: Three sisters were diagnosed with ALMS1-related Alström syndrome; in one proband, mosaic and germline deletions at the 17q11.2 region were identified, and a novel homozygous nonsense variant in the VSX2 gene was detected in family members with vision loss. This study aims to present the clinical and molecular characteristics of these three rare genetic events occurring within the same family. METHODS: Physical examination, imaging, developmental assessment, and biochemical tests were performed on the probands and family members. Genetic analyses included conventional karyotyping, SNP array, and whole exome sequencing (WES). RESULTS: A novel homozygous nonsense variant (c.6288T > A, p.Tyr2096Ter) in the ALMS1 gene, not previously reported, was identified in the three sisters. In proband 1, a 998 kb mosaic deletion encompassing the gene (~ 80–85% mosaicism) and an additional 310 kb germline deletion not including NF1 were detected at the 17q11.2 locus. A novel homozygous nonsense variant (c.753G > A, p.Trp251Ter) in the VSX2 gene was found in the vision-impaired maternal uncle and aunt. CONCLUSION: This study is the first to report the coexistence of a novel ALMS1 variant causing Alström syndrome, mosaic and germline deletions at the 17q11.2 region, and a novel pathogenic variant in the VSX2 gene within the same family. These findings highlight the importance of expanded genetic analyses and comprehensive evaluation of family members in diagnosing rare diseases.