Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

TY - JOUR

T1 - Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

AU - van der Ven, Amelie T

AU - Connaughton, Dervla M

AU - Ityel, Hadas

AU - Mann, Nina

AU - Nakayama, Makiko

AU - Chen, Jing

AU - Vivante, Asaf

AU - Hwang, Daw-Yang

AU - Schulz, Julian

AU - Braun, Daniela A

AU - Schmidt, Johanna Magdalena

AU - Schapiro, David

AU - Schneider, Ronen

AU - Warejko, Jillian K

AU - Daga, Ankana

AU - Majmundar, Amar J

AU - Tan, Weizhen

AU - Jobst-Schwan, Tilman

AU - Hermle, Tobias

AU - Widmeier, Eugen

AU - Ashraf, Shazia

AU - Amar, Ali

AU - Hoogstraaten, Charlotte A

AU - Hugo, Hannah

AU - Kitzler, Thomas M

AU - Kause, Franziska

AU - Kolvenbach, Caroline M

AU - Dai, Rufeng

AU - Spaneas, Leslie

AU - Amann, Kassaundra

AU - Stein, Deborah R

AU - Baum, Michelle A

AU - Somers, Michael J G

AU - Rodig, Nancy M

AU - Ferguson, Michael A

AU - Traum, Avram Z

AU - Daouk, Ghaleb H

AU - Bogdanović, Radovan

AU - Stajić, Natasa

AU - Soliman, Neveen A

AU - Kari, Jameela A

AU - El Desoky, Sherif

AU - Fathy, Hanan M

AU - Milosevic, Danko

AU - Al-Saffar, Muna

AU - Awad, Hazem S

AU - Eid, Loai A

AU - Selvin, Aravind

AU - Senguttuvan, Prabha

AU - Sanna-Cherchi, Simone

AU - Rehm, Heidi L

AU - MacArthur, Daniel G

AU - Lek, Monkol

AU - Laricchia, Kristen M

AU - Wilson, Michael W

AU - Mane, Shrikant M

AU - Lifton, Richard P

AU - Lee, Richard S

AU - Bauer, Stuart B

AU - Lu, Weining

AU - Reutter, Heiko M

AU - Tasic, Velibor

AU - Shril, Shirlee

AU - Hildebrandt, Friedhelm

N1 - Copyright © 2018 by the American Society of Nephrology.

PY - 2018/9

Y1 - 2018/9

N2 - BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

AB - BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

KW - Animals

KW - Genetic Predisposition to Disease/epidemiology

KW - Humans

KW - Incidence

KW - Kidney/abnormalities

KW - Mice

KW - Pedigree

KW - Phenotype

KW - Prognosis

KW - Risk Assessment

KW - Sensitivity and Specificity

KW - Sex Distribution

KW - Urinary Tract/abnormalities

KW - Urogenital Abnormalities/epidemiology

KW - Vesico-Ureteral Reflux/epidemiology

KW - Whole Exome Sequencing/methods

U2 - 10.1681/ASN.2017121265

DO - 10.1681/ASN.2017121265

M3 - SCORING: Journal article

C2 - 30143558

VL - 29

SP - 2348

EP - 2361

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 9

ER -