Open AccessWhole-exome sequencing of a novel initiation codon mutation in RUNX2 in a Chinese family with cleidocranial dysplasia
Author(s) -
Lei Yang,
Genqi Lu,
Shen Weishou,
Wenjing Chen,
Haiyan Lu,
Guozhong Zhang,
Shuo Yuan,
Shushen Zheng,
Jiabao Ren
Publication year - 2021
Publication title -
medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 148
eISSN - 1536-5964
pISSN - 0025-7974
DOI - 10.1097/md.0000000000027746
Subject(s) - cleidocranial dysplasia , genetics , exome sequencing , medicine , mutation , sanger sequencing , haploinsufficiency , proband , single nucleotide polymorphism , biology , gene , genotype , supernumerary , anatomy , phenotype
Cleidocranial dysplasia (CCD) is mainly attributable to a variant of runt-related transcription factor 2 ( RUNX2 ) on chromosome 6p21. CCD is an autosomal dominant skeletal disorder characterized by open/delayed closure of fontanels, clavicular hypoplasia, retention of deciduous teeth, and supernumerary permanent teeth. The aim of this study was to investigate potentially pathogenic mutations in 2 Chinese families. Genomic DNA was obtained from peripheral blood lymphocytes, and whole exome sequencing and Sanger sequencing were performed to detect gene variants. Real-time quantitative PCR was performed to determine the mRNA expression level of RUNX2 in the proband of family 1. Silico algorithms and conservation analyses were used to evaluate the functional impact. We identified a novel initiation codon mutation (c.2T>C) and a previously reported mutation (c.569G>A). Familial co-segregation verified an autosomal-dominant inheritance pattern. Our findings demonstrated that the novel mutation c.2T>C causes CCD. Quantitative real-time PCR suggested that downregulated RUNX2 levels and haploinsufficiency in RUNX2 lead to CCD. These results extend the spectrum of RUNX2 mutations in CCD patients and can be used for genetic consultation and prenatal diagnosis.