Recessive multiple epiphyseal dysplasia and Stargardt disease in two sisters

Background: The rapid spread of genome-wide next-generation sequencing in the molecular diagnosis of rare genetic disorders has produced increasing evidence of multilocus genomic variations in cases with a previously well-characterized molecular diagnosis. Here, we describe two patients with a rare combination of skeletal abnormalities and retinal dystrophy caused by variants in the SLC26A2 and ABCA4 genes, respectively, in a family with parental consanguinity. Methods: Next-generation sequencing and Sanger sequencing were performed to obtain a molecular diagnosis for the retinal and skeletal phenotypes, respectively. Results: Genetic testing revealed that the sisters were homozygous for the p.(Cys653Ser) variant in SLC26A2 and heterozygous for the missense p.(Pro68Leu) and splice donor c.6386+2C>G variants in ABCA4. Segregation analysis confirmed the carrier status of the parents. Conclusion: Despite low frequency of occurrence, the detection of multilocus genomic variations in a single disease gene-oriented approach can provide accurate diagnosis even in cases with high phenotypic complexity. A targeted sequencing approach can detect relationships between observed phenotypes and underlying genotypes, useful for clinical management.

Automated summary

This study identified two sisters in a family with rare genetic disorders using next-generation sequencing and Sanger sequencing, confirming the genetic mutations responsible for their conditions and further verifying the carrier status of their parents. The findings suggest that the detection of multilocus genomic variations can provide accurate diagnosis even in cases with high phenotypic complexity. A targeted sequencing approach can be useful for clinical management by uncovering the relationships between observed phenotypes and underlying genotypes.