PDF(Pubmed)
Abstract：
BACKGROUND: Mutations in PTH1R are associated with Jansen-type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation.
METHODS: The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software.
RESULTS: High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic.
CONCLUSIONS: We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.
METHODS: The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software.
RESULTS: High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic.
CONCLUSIONS: We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.
摘要：
背景：PTH1R中的突变与Jansen型干phy端软骨发育不良（JMC）有关，Blomstrand骨软骨发育不良（BOCD），艾肯综合征,内生软骨瘤,和牙齿萌出（PFE）的原发性失败。PTH1R基因的遗传可以是常染色体显性遗传或常染色体隐性遗传，表明了基因的复杂性.我们的目的是鉴定具有新型PTH1R突变的家族成员的表型差异。
方法：先证者为13年，6个月大的女孩身材矮小，牙齿异常萌出,骨骼发育不良,脸中部发育不全.先证者的兄弟和父亲身材矮小，牙齿萌出异常。对先证者进行高通量测序，并且通过Sanger测序在先证者和其他家庭成员中确认了该变体。使用ClustalX软件进行氨基酸序列比对。使用I-TASSER网站和PyMOL软件分析和显示三维结构。
结果：高通量基因组测序和Sanger测序验证表明，先证者，她的父亲,和她的兄弟都携带PTH1R（NM_000316）c.1393G>A（p。E465K）突变。c.1393G>A（p。E465K）突变是新的，因为它没有在文献数据库中报道。根据美国医学遗传学和基因组学学院（ACMG）的指南，p.E465K变异体被认为具有不确定的意义.生物学信息分析表明，该鉴定的变体高度保守且极有可能致病。
结论：我们在PTH1R基因中发现了一种新的杂合突变，导致临床表现不完全外显率，扩大了已知PTH1R突变的范围。
方法：先证者为13年，6个月大的女孩身材矮小，牙齿异常萌出,骨骼发育不良,脸中部发育不全.先证者的兄弟和父亲身材矮小，牙齿萌出异常。对先证者进行高通量测序，并且通过Sanger测序在先证者和其他家庭成员中确认了该变体。使用ClustalX软件进行氨基酸序列比对。使用I-TASSER网站和PyMOL软件分析和显示三维结构。
结果：高通量基因组测序和Sanger测序验证表明，先证者，她的父亲,和她的兄弟都携带PTH1R（NM_000316）c.1393G>A（p。E465K）突变。c.1393G>A（p。E465K）突变是新的，因为它没有在文献数据库中报道。根据美国医学遗传学和基因组学学院（ACMG）的指南，p.E465K变异体被认为具有不确定的意义.生物学信息分析表明，该鉴定的变体高度保守且极有可能致病。
结论：我们在PTH1R基因中发现了一种新的杂合突变，导致临床表现不完全外显率，扩大了已知PTH1R突变的范围。
