应用二代基因测序检测成年起病特发性甲状旁腺功能减退症的致病基因

A genomic study of adult-onset idiopathic hypoparathyroidism in Chinese by targeted next-generation sequencing

目的 初步探索单基因突变在成年起病甲状旁腺功能减退症发病机制中的作用,并探索二代基因测序在其中的应用价值.方法 共纳入17例成年起病的特发性甲状旁腺功能减退症（IHP）患者,其中9例患者血钙低于正常时即出现24h尿钙升高,8例为初诊的未治疗患者.收集其临床资料,采用二代基因测序分析其是否存在基因突变.结果 1例患者检出一种新的GCMB基因纯合突变[c.130G ＞A （p.G44S）],突变率为5.9％,Polyphen 2软件预测该突变引起所编码的蛋白质结构和功能的损害预测值为0.999.该患者为36岁女性,以“发作性四肢搐搦10年”就诊,初诊时血钙1.48mmol/L,血磷2.29mmol/L,甲状旁腺素（PTH） ＜3.0ng/L,合并白内障和颅内钙化,治疗后出现高钙尿症,无泌尿系结石,无甲状旁腺功能减退症家族史或其他发育异常表现.结论 对于成年起病的非手术性孤立性甲状旁腺功能减退症患者,基因突变检出率较低.单基因突变尽管不常见,但临床医师应关注可能的由基因突变所致的甲状旁腺功能减退症。

Objective Several genes have been recognized to be associated with non-surgical hypoparathyroidism.Data about gene mutations in adult-onset hypoparathyroidism patients is lacking.This study was designed to screen gene mutation in adult-onset hypoparathyroidism in Chinese through the targeted next-generation sequencing （NGS）.Methods We recruited 17 patients with adult-onset hypoparathyroidism who were regularly followed or newly diagnosed at our centre during the past one year.Nine of them developed hypercalciuria during the treatment with calcium and vitamin D.Eight of them were newly diagnosed with no treatment.Targeted NGS was performed to screen 11 related genes,including AIRE,AP2S1,CASR,CLDN16,FAM111A,GATA3,GCM2,PTH,TBCE,TBX1 and TRPM6.Results A novel homozygosis mutation of GCMB gene[c.130G 〉 A （p.G44S）] was identified which was predicted to be deleterious by PolyPhen2.The patient was a 36-year-old woman who suffered from paroxysmal carpopedal spasms for ten years.Before treatment,the serum calcium and phosphorus was 1.48 mmol/L and 2.29 mmol/L,respectively.Parathyroid hormonel （PTH） concentration was lower than 3.0 ng/L.Intracranial calcification and cataract were also identified.She developed hypercalciuria during treatment with calcium and vitamin D.She had no physical deformity or family history of hypoparathyroidism.Conclusions In this study,the genetic defect was only identified in 1 patient （5.9%）.In adult-onset hypoparathyroidism without other diagnostic clues,the gene mutation screening as the first choice to clarify the etiology was not recommended.