A novel heterozygous mutation in PTHLH causing autosomal dominant brachydactyly type E complicated with short stature

Background Brachydactyly type E (BDE) is a general term characterized by variable shortening of metacarpals and metatarsals, with phalanges affected frequently. It can occur as an isolated form or part of syndromes and manifest a high degree of phenotypic variability. In this study, we have identified the clinical characteristics and pathogenic causes of a four‐generation pedigree with 10 members affected by BDE and short stature. Methods After the informed consent was signed, clinical data and peripheral blood samples were collected from available family members. Karyotype analysis, array‐CGH, next‐generation sequencing, and Sanger sequencing were employed to identity the pathogenic candidate gene. Results No translocation or microdeletion/duplication was found in karyotype analysis and array‐CGH; hence, a novel heterozygous mutation, c.146dupA. p.S50Vfs*22, was detected by next‐generation sequencing in PTHLH gene, leading to a premature stop codon. Subsequently, the mutation was confirmed by Sanger sequencing and co‐segregation analysis. Conclusion In this study, we described a novel heterozygous mutation (c.146dupA. p.S50Vfs*22) of gene PTHLH in a Chinese family. The mutation could induce a premature stop codon leading to a truncation of the protein. Our study broadened the mutation spectrum of PTHLH in BDE. (A) No obvious chromosome aberration was found in the affected individuals. (B) Direct sequencing of PTHLH exons showing heterozygous c.146dupA, p.S50Vfs*22 mutation identified in BDE affected individuals (II2, III6, III16, III17, IV11) but not in normal family members (III5, IV2). (C) Evolutionary conservation of the cluster across multiple species.