Co-occurrence of two monogenic diseases within a single family

Kindler epidermolysis bullosa (KEB), a rare genodermatosis caused by loss-of-function mutations in the FERMT1 gene (encoding kindlin-1), is clinically characterized by congenital blistering, skin atrophy, poikiloderma, photosensitivity, and an increased predisposition to cutaneous squamous cell carcinoma (cSCC). Hearing loss, a common sensory impairment with multifactorial origins, often stems from genetic or environmental factors. Here, we report a unique familial case in which one sibling has KEB complicated by cSCC, and the other has congenital autosomal recessive non-syndromic hearing loss (ARNSHL). To describe the co-occurrence of KEB and ARNSHL in a single family and emphasize the utility of next-generation sequencing (NGS) for precise genetic diagnosis. NGS-based approaches (gene panel and whole-exome sequencing) were used to screen for pathogenic variants in two affected siblings. Sanger sequencing validated variant segregation with disease phenotypes and was used to assessed pathogenicity in family members. Genetic analysis identified a novel homozygous nonsense mutation, c.T240A (p.Y80X), in FERMT1 in the KEB patient, consistent with molecular characteristics of loss-of-function. The ARNSHL-affected sibling carried a novel homozygous missense mutation, c.T4469C (p.F1490S), in MYO15A, a gene critical for auditory hair cell function. Both variants followed autosomal recessive inheritance and were absent in population databases. This study highlights the power of NGS in diagnosing genetically distinct disorders without shared pathogenic mechanisms within a single family. Our findings underscore the clinical value of comprehensive genomic sequencing for unravelling complex hereditary conditions, especially when multiple rare disorders segregate independently in kindreds.