目的　鉴定导致假性甲状旁腺功能减退症（PHP）Ia型发病的GNAS基因突变。方法　回顾分析1例PHP-Ia型 患儿的临床资料。利用Sanger测序方法对患儿及其父母GNAS基因的13外显子进行检测。疑似致病突变在478例健康对 照者中进行筛查，排除非致病性变异。利用深度测序方法对患儿及其父母外周静脉血的DNA进行测序，分析确定致病突 变的起源。结果　女性患儿，实验室检查结果示低血钙、高血磷及高甲状旁腺素（PTH）；体格检查有Albright遗传性骨营 养不良（AHO）畸形。临床表现符合PHP-Ia型特征。GNAS基因突变筛查发现1个尚未见报道的，位于6号外显子的错义突 变（c.479G>C，p. R160P）。 父母及健康对照均者未发现该突变。针对突变所在的GNAS基因6号外显子在患儿及其父母 外周静脉血的DNA中进行深度测序，每个样本均获得8 000条左右的序列。患儿父母的所有序列中均筛查到该突变。患儿 序列中，3 984条携带G等位基因，4 019条携带C等位基因，两者的数目大致相同。深度测序的结果提示，该突变是来源于 母系生殖细胞的新发突变。结论　发现一个导致PHP-Ia型发生的GNAS基因新突变（c.479G>C，p.R160P），推测该突变 起源于母亲生殖细胞。

　Objective　To identify the GNAS gene mutation resulting in pseudohypoparathyroidism type Ia (PHP-Ia) in one patient. Methods　The clinical data of a patient with pseudohypoparathyroidism type Ia was retrospectively analyzed. All the 13 exons of GNAS were sequenced using Sanger method for the patient and the parents. The distribution of suspected causal mutation was screened in 478 healthy controls. To clarify the origin of the mutation, we performed targeted high-depth sequencing of GNAS exon harboring the mutation for the patient and the parents. Results　The clinical data of the patient with the laboratory results of hypocalcaemia, hyperphosphataemia, elevated serum PTH, together with the features of AHO, conformed to the characterization of PHP-Ia. The sequencing of GNAS exons identified a missense mutation (c.479G>C, p.R160P) located at exon 6 in the patient, which was absent in DNA of the parents. The mutation was not reported previously and was not found in the 478 healthy controls. We obtained about  8000-fold coverage from high-depth sequencing of DNA from peripheral blood of the patient and the parents. The disease-associated allele C identified in the patient was not observed in the parents. The number of reads with G allele (3984 reads) was roughly equal to that of C allele (4019 reads) from the targeted reanalysis of DNA of the patient. The results from high-depth sequencing indicated a de novo mutation in maternal germ cells. Conclusions　We identified a new GNAS gene mutation (c.479G>C, p.R160P) caused PHP-Ia in a patient. Our results suggested the mutation was a maternal germline de novo mutation.