Pathogenic variant of DYNC2H1 associated with lingual hamartoma in a Chinese pedigree

Background Molecular etiology of lingual hamartoma is poorly understood. This study aims to identify potentially deleterious mutations for lingual hamartoma and analyze its molecular profile by a combination of whole‐exome sequencing and RNA‐sequencing. Methods Whole‐exome sequencing was conducted on the proband presenting lingual hamartoma and patient's unaffected family members. Potentially pathogenic mutations were identified after filtration. The pathogenicity of the identified variants was predicted by in silico algorithms and conservative analysis. RNA‐sequencing was performed to further explore the molecular profile of lingual hamartoma. Results Whole‐exome sequencing of the proband and patients' unaffected brother and parents identified a de novo mutation c.931C>T_p.Pro311Ser in the DYNC2H1 gene (NM_001080463.2). The DYNC2H1 mutation was predicted to be disease‐causing for affecting highly conserved amino acid by PolyPhen2 and Mutation Taster. RNA‐sequencing analysis showed that the DYNC2H1 gene was significantly down‐regulated in lingual hamartoma. Gene set enrichment analysis revealed cilium assembly and Hedgehog signaling pathway were significantly affected. Conclusion The study expanded our knowledge on the clinical and genetic spectrum of lingual hamartoma by identifying causal variants in a Chinese pedigree. DYNC2H1 is likely to participate in tongue development and its pathologic mutation may underlie the etiology of lingual hamartoma.