Frequent <i>FBN2</i> variants in pectus excavatum highlight underlying phenotypic variability.

Abstract

During genetic screening for radioulnar synostosis (RUS), we identified <i>FBN2</i> variants in individuals who also exhibited pectus excavatum (PE). This study aimed to investigate the association between <i>FBN2</i> variants and non-syndromic paediatric PE. We phenotyped an <i>Fbn2</i> knockout mouse model. A cohort of 290 paediatric PE probands and their families was recruited. Comprehensive analyses included karyotyping, copy number variation arrays, exome sequencing (ES), Sanger sequencing validation and systematic clinical re-evaluation using the Callewaert scoring system. Statistical burden analysis was performed against 4961 ethnicity-matched ES controls. Gene expression was assessed via fluorescence in situ hybridisation, and Bone Morphogenetic Protein (BMP) signalling activity was examined through immunohistochemistry in murine sternal tissues. <i>Fbn2</i>-deficient mice exhibited sternal abnormalities and a PE-like phenotype, without evidence of rib overgrowth. In the human cohort, ES identified 15 rare damaging <i>FBN2</i> variants, including three de novo and three familial cases, distributed across the entire gene. Burden analysis confirmed a significant association between <i>FBN2</i> variants and PE (OR=5.276, 95% CI 2.918 to 9.541, p<0.001). Clinical re-evaluation revealed only mild connective tissue features in carriers, with RUS observed in just one individual. Genotype-phenotype analysis showed minimal overlap between PE and RUS phenotypes, highlighting broad variability. Mechanistically, reduced BMP-SMAD1/5/8 signalling was observed in the sternal ossification centres of <i>Fbn2</i>-mutant mice. Our findings establish <i>FBN2</i> as a significant genetic contributor to isolated PE and underscore the broad phenotypic spectrum and high clinical variability of <i>FBN2</i>-related disorders.