Genetic characteristics associated with isolated Microtia revealed through whole exome sequencing of 201 pedigrees.

Microtia is one of the most common congenital craniofacial malformations, characterized by the maldevelopment of the external and middle ear. While numerous genes have been implicated in syndromic forms of microtia, the genetic underpinnings of isolated microtia remain poorly understood. In this study, we conducted whole exome sequencing (WES) on 201 pedigrees with isolated microtia to investigate its genetic basis. Bioinformatics analysis identified 1362 deleterious variants corresponding to 332 candidate genes, including 40 previously associated with microtia-related phenotypes. Among these, variants in FOXI3, the most frequently identified pathogenic gene for isolated microtia so far, were detected. Remarkably, the remaining 39 genes, which have been recognized as pathogenic in syndromes with microtia, are also suggested to play a role in isolated microtia. However, the precise molecular mechanisms by which these genes contribute to microtia remain to be elucidated. Furthermore, through protein-protein interaction network analysis, functional annotation, and zebrafish expression profiling, we identified two novel genes, MCM2 and BDNF, as the most promising contributors to the pathogenesis of isolated microtia. Our findings, based on the largest WES study of isolated microtia pedigrees to date, provide new insights into the genetic architecture of isolated microtia and suggest promising avenues for future research.