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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
JournalHuman Genetics
DOIs
Publication statusPublished - 2019 Jan 1

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Nephrolithiasis
Mutation
Genes
Pakistan
Recessive Genes
Consanguinity
Mutation Rate
Age of Onset
Tertiary Care Centers
Exons
Phosphates
Morbidity
Recurrence

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Amar, Ali ; Majmundar, Amar J. ; Ullah, Ihsan ; Afzal, Ayesha ; Braun, Daniela A. ; Shril, Shirlee ; Daga, Ankana ; Jobst-Schwan, Tilman ; Ahmad, Mumtaz ; Sayer, John A. ; Gee, Heon Yung ; Halbritter, Jan ; Knöpfel, Thomas ; Hernando, Nati ; Werner, Andreas ; Wagner, Carsten ; Khaliq, Shagufta ; Hildebrandt, Friedhelm. / Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. In: Human Genetics. 2019.
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abstract = "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.",
author = "Ali Amar and Majmundar, {Amar J.} and Ihsan Ullah and Ayesha Afzal and Braun, {Daniela A.} and Shirlee Shril and Ankana Daga and Tilman Jobst-Schwan and Mumtaz Ahmad and Sayer, {John A.} and Gee, {Heon Yung} and Jan Halbritter and Thomas Kn{\"o}pfel and Nati Hernando and Andreas Werner and Carsten Wagner and Shagufta Khaliq and Friedhelm Hildebrandt",
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Amar, A, Majmundar, AJ, Ullah, I, Afzal, A, Braun, DA, Shril, S, Daga, A, Jobst-Schwan, T, Ahmad, M, Sayer, JA, Gee, HY, Halbritter, J, Knöpfel, T, Hernando, N, Werner, A, Wagner, C, Khaliq, S & Hildebrandt, F 2019, 'Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis', Human Genetics. https://doi.org/10.1007/s00439-019-01978-x

Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. / Amar, Ali; Majmundar, Amar J.; Ullah, Ihsan; Afzal, Ayesha; Braun, Daniela A.; Shril, Shirlee; Daga, Ankana; Jobst-Schwan, Tilman; Ahmad, Mumtaz; Sayer, John A.; Gee, Heon Yung; Halbritter, Jan; Knöpfel, Thomas; Hernando, Nati; Werner, Andreas; Wagner, Carsten; Khaliq, Shagufta; Hildebrandt, Friedhelm.

In: Human Genetics, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis

AU - Amar, Ali

AU - Majmundar, Amar J.

AU - Ullah, Ihsan

AU - Afzal, Ayesha

AU - Braun, Daniela A.

AU - Shril, Shirlee

AU - Daga, Ankana

AU - Jobst-Schwan, Tilman

AU - Ahmad, Mumtaz

AU - Sayer, John A.

AU - Gee, Heon Yung

AU - Halbritter, Jan

AU - Knöpfel, Thomas

AU - Hernando, Nati

AU - Werner, Andreas

AU - Wagner, Carsten

AU - Khaliq, Shagufta

AU - Hildebrandt, Friedhelm

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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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