CaSR基因新发杂合突变所致家族性低尿钙性高钙血症一家系分析

One pedigree analysis of a familial hypocalciuric hypercalcemia caused by a new heterozygous mutation in calcium-sensing receptor gene

采集病史了解1例家族性低尿钙性高钙血症（familial hypocalciuric hypercalcemia, FHH）患儿的临床表现、生长发育状况，同时收集其父母及3名母系亲属的临床资料。检测血清甲状旁腺素（PTH）、血钙、血磷、24 h尿钙、24 h尿钙/尿肌酐清除率（urinary calcium to creatinine ratio，UCCR）；并采集其外周血标本，提取基因组DNA，采用全基因外显子组测序检测先证者基因突变，并通过Sanger测序验证其家系的突变位点，分析基因型与临床表型的关系。结果显示，先证者运动发育落后伴重度高钙血症（最高4.20 mmol/L），其母亲无症状，血钙处于正常范围上限（2.57 mmol/L），但两者均存在低尿钙（UCCR均〈0.01）。全外显子测序发现患儿钙敏感受体（calcium-sensing receptor，CaSR）基因4号外显子存在第1243位核苷酸C转换为T的杂合错义突变，导致其编码的第415位氨基酸由精氨酸变异为色氨酸（R415W）。Sanger测序证实该突变来源于其母，其他家系成员未发现突变。

Medical history and physical examinations were performed to assess the clinical manifestations and growth of one patient with familial hypocalciuric hypercalcemia（FHH）. Clinical data, including histories of his parents and 3 maternal relatives were collected. Serum parathyroid hormone（PTH）, calcium, phosphorus, 24-hour urinary calcium, and 24-hour urinary calcium to creatinine ratio（UCCR）were measured or calculated. Meanwhile, after peripheral blood samples were collected and genomic DNA was extracted, the whole exome sequencing to detect gene mutations of the proband was performed. Further family screenings were also performed by Sanger sequencing to assess the relationship between genotype and phenotype. The results showed that the proband with motor developmental delays had severe hypercalcemia（4.20 mmol/L）, while his mother without clinical symptoms had a higher blood calcium within the normal range（2.57 mmol/L）. However, their urinary calcium levels were both low（UCCR〈 0.01）. The C→T heterozygous missense mutation was found by exome sequencing at nucleotide 1243 within exon 4 of calcium sensing receptor（CaSR）gene in the proband, which caused a substitution of Arginine to Tryptophan（R415W）. Sanger sequencing confirmed the same mutation in his mother. There was no mutation in other family members.