The Complexity of Familial Inheritance in Pectus Excavatum: A Ten-Family Exome Sequencing Analysis

作者：Juan Farina, Rory J. Olson, Radhika Dhamija, Anne Bofferding, Aleksandar Sekulić, Jan B. Egan, Dawn E. Jaroszewski · 发表于：Genes · 年份：2024 · DOI：10.3390/genes15111429 · 被引用次数：4 · 研究领域：Pectus Deformity Diagnosis and Treatment、Genital Health and Disease、Congenital limb and hand anomalies

Background/Objectives: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors. Methods: Family members with a confirmed PEx diagnosis (one proband and two first-degree relatives) and non-affected members were recruited into this study. Exome sequencing was performed on all affected familial PEx cases to systematically screen for candidate genes that are likely to be causative for PEx, and on non-affected family members for variant segregation analysis. Results: Ten families, with three affected members each, participated, providing thirty familial PEx cases. Different inheritance patterns were represented across the ten pedigrees, with possible incomplete penetrance. Genetic variants in REST (essential for neuronal development and associated with pectus deformities in prior studies), SMAD4 (variants can predispose individuals to thoracic aortic diseases), and COL5A (associated with Ehlers–Danlos syndrome and Fibromuscular dysplasia) were initially identified as potentially linked to the development of pectus deformities and segregated with the phenotype. No variants were shared across families in the studied population. Conclusions: Germline exome sequencing of families with multiple individuals af...