Identification of a novel pathogenic variant in MYLK in an Iranian family with non-syndromic familial aortic aneurysm and dissection by whole-exome sequencing and literature review.

backgroundNon-syndromic familial thoracic aortic aneurysm and dissection (ns-FTAAD) is an inherited disease that follows an autosomal dominant pattern; however, pinpointing the responsible genes is often complex. The MYLK gene has been identified as one implicated in TAAD, which necessitates careful and specialized clinical oversight. Systematically gathering evidence on the disease-causing potential of rare genetic variants through detailed family studies is crucial for developing more effective treatment protocols for individuals with this life-threatening hereditary condition. This study reports the identification of a novel pathogenic variant causing ns-FTAAD and provides a comprehensive review of all associated TAAD variants.

methodsWe report an Iranian family with ns-FTAAD associated with a novel MYLK germline variant. We evaluated all relevant clinical and genetic information. Whole-exome sequencing (WES) was used for variant detection, and Sanger sequencing was performed for validation. A literature search for all TAAD types was conducted on PubMed. The extracted data included the total number of patients studied, the subset with MYLK variants, specific nucleotide and protein changes, patient demographics, pathological features, and clinical symptoms.

resultsExome sequencing led to the identification of a novel variant, NM_053025.4:c.2208_2230dup (p.Ile744Argfs*9), that led to a premature stop codon and nonsense-mediated decay. Five people were variant carriers and three people were non-carriers. A total of 1,440 patients clinically diagnosed with TAAD were recruited in these studies, among whom 59 were carriers of an MYLK variant. Among the 34 variants collected, the distribution was as follows: missense (58.82%), frameshift (14.71%), splicing (5.88%), CNVs (5.88%), and other (14.71%).

conclusionOur study expands the mutational landscape of MYLK-related ns-FTAAD with a novel pathogenic variant. The aggregation of all reported cases highlights that while missense variants predominate, loss-of-function mechanisms like frameshift variants are a significant cause of disease. These findings are crucial for risk assessment, familial screening, and the clinical management of affected families.