Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis
Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis
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DOI：
10.1007/s00439-019-01978-x
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发表时间：
2019-03-01
期刊：
影响因子：
5.3
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
Amar, Ali;Majmundar, Amar J.;Hildebrandt, Friedhelm
肾结石（NL）影响全球1/11的个体，并导致显著的患者发病率。我们以前证明了NL的遗传原因可以在11-29%的主要是美国和欧洲的结石形成者中确定。巴基斯坦位于亚非石带，肾结石患病率高（12%），近亲结婚率高（>50%）。我们从巴基斯坦旁遮普省的五家三级医院招募了235名因肾结石住院的巴基斯坦受试者。调查受试者的发病年龄、NL复发和家族史。我们对30个NL疾病基因进行了高通量外显子测序和变异分析，以确定每个受试者的单基因致病突变。我们在30个疾病基因中的4个中检测到可能的致病突变，在7%（235个中的17个）的NL家族中产生可能的分子诊断。在常染色体隐性遗传病基因中，17个致病突变中只有1个被确定。12个突变中有10个为新突变（83%）。SLC 34 A1是最常见的突变（17个解决的家庭中有12个）。我们观察到具有阳性NL家族史的受试者（13/109，12%）的致病突变频率高于具有阴性家族史的受试者（4/120，3%）。通过遗传分析鉴定的5个错义SLC 34 A1变体表现出磷酸盐转运缺陷。我们在一个新的地理队列中研究了NL的单基因原因，并在功能验证中最常发现钠磷酸盐转运蛋白SLC 34 A1的显性突变。
Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant patient morbidity. We previously demonstrated a genetic cause of NL can be identified in 11-29% of pre-dominantly American and European stone formers. Pakistan, which resides within the Afro-Asian stone belt, has a high prevalence of nephrolithiasis (12%) as well as high rate of consanguinity (>50%). We recruited 235 Pakistani subjects hospitalized for nephrolithiasis from five tertiary hospitals in the Punjab province of Pakistan. Subjects were surveyed for age of onset, NL recurrence, and family history. We conducted high-throughput exon sequencing of 30 NL disease genes and variant analysis to identify monogenic causative mutations in each subject. We detected likely causative mutations in 4 of 30 disease genes, yielding a likely molecular diagnosis in 7% (17 of 235) of NL families. Only 1 of 17 causative mutations was identified in an autosomal recessive disease gene. 10 of the 12 detected mutations were novel mutations (83%). SLC34A1 was most frequently mutated (12 of 17 solved families). We observed a higher frequency of causative mutations in subjects with a positive NL family history (13/109, 12%) versus those with a negative family history (4/120, 3%). Five missense SLC34A1 variants identified through genetic analysis demonstrated defective phosphate transport. We examined the monogenic causes of NL in a novel geographic cohort and most frequently identified dominant mutations in the sodium-phosphate transporter SLC34A1 with functional validation.