Frequent FBN2 variants in pectus excavatum highlight underlying phenotypic variability

During genetic screening for radioulnar synostosis (RUS), we identified FBN2 variants in individuals who also exhibited pectus excavatum (PE). This study aimed to investigate the association between FBN2 variants and non-syndromic paediatric PE.

We phenotyped an Fbn2 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.

Fbn2-deficient mice exhibited sternal abnormalities and a PE-like phenotype, without evidence of rib overgrowth. In the human cohort, ES identified 15 rare damaging FBN2 variants, including three de novo and three familial cases, distributed across the entire gene. Burden analysis confirmed a significant association between FBN2 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 Fbn2-mutant mice.

Our findings establish FBN2 as a significant genetic contributor to isolated PE and underscore the broad phenotypic spectrum and high clinical variability of FBN2-related disorders.