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Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis

 Ali Amar  ;  Amar J. Majmundar  ;  Ihsan Ullah  ;  Ayesha Afzal  ;  Daniela A. Braun  ;  Shirlee Shril  ;  Ankana Daga  ;  Tilman Jobst-Schwan  ;  Mumtaz Ahmad  ;  John A. Sayer  ;  Heon Yung Gee  ;  Jan Halbritter  ;  Thomas Knöpfel  ;  Nati Hernando  ;  Andreas Werner  ;  Carsten Wagner  ;  Shagufta Khaliq  ;  Friedhelm Hildebrandt 
 Human Genetics, Vol.138(3) : 211-219, 2019 
Journal Title
 Human Genetics 
Issue Date
Adolescent ; Adult ; Aged ; Alleles ; Animals ; Child ; Child, Preschool ; Cohort Studies ; DNA Mutational Analysis ; Family ; Female ; Gene Expression Profiling*/methods ; Genetic Association Studies* ; Genetic Predisposition to Disease* ; Genotype ; Geography, Medical ; High-Throughput Nucleotide Sequencing ; Humans ; Infant ; Male ; Middle Aged ; Mutation ; Nephrolithiasis/epidemiology* ; Nephrolithiasis/genetics* ; Pakistan/epidemiology ; Sodium-Phosphate Cotransporter Proteins, Type IIa/genetics ; Xenopus laevis ; Young Adult
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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