Jaroszewski, Dawn E.

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 affected by PEx in our study identified potential gene candidates linked to PEx. These candidates are private to individual families and no strong candidates shared across multiple families were identified. These findings suggest that the inheritance of PEx may not be strongly related to a shared single genetic variant in known genes. Given the accumulating evidence for the genetic basis of familial PEx, further studies, including polygenic analyses, as well as assessment of the non-coding genome and possible epigenetic markers are warranted.

Background Pectus excavatum is the most common chest wall deformity. There is still controversy about cardiopulmonary limitations of this disease and benefits of surgical repair. This study evaluates the impact of pectus excavatum on the cardiopulmonary function of adult patients before and after a modified minimally invasive repair. Methods and Results In this retrospective cohort study, an electronic database was used to identify consecutive adult (aged ≥18 years) patients who underwent cardiopulmonary exercise testing before and after primary pectus excavatum repair at Mayo Clinic Arizona from 2011 to 2020. In total, 392 patients underwent preoperative cardiopulmonary exercise testing; abnormal oxygen consumption results were present in 68% of patients. Among them, 130 patients (68% men, mean age, 32.4±10.0 years) had post‐repair evaluations. Post‐repair tests were performed immediately before bar removal with a mean time between repair and post‐repair testing of 3.4±0.7 years (range, 2.5–7.0). A significant improvement in cardiopulmonary outcomes ( P <0.001 for all the comparisons) was seen in the post‐repair evaluations, including an increase in maximum, and predicted rate of oxygen consumption, oxygen pulse, oxygen consumption at anaerobic threshold, and maximal ventilation. In a subanalysis of 39 patients who also underwent intraoperative transesophageal echocardiography at repair and at bar removal, a significant increase in right ventricle stroke volume was found ( P <0.001). Conclusions Consistent improvements in cardiopulmonary function were seen for pectus excavatum adult patients undergoing surgery. These results strongly support the existence of adverse cardiopulmonary consequences from this disease as well as the benefits of surgical repair.