@article {752, title = {Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis.}, journal = {Kidney Int}, volume = {97}, year = {2020}, month = {2020 03}, pages = {567-579}, abstract = {

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70\% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59\%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2019.09.026}, author = {Jobst-Schwan, Tilman and Kl{\"a}mbt, Verena and Tarsio, Maureen and Heneghan, John F and Majmundar, Amar J and Shril, Shirlee and Buerger, Florian and Ottlewski, Isabel and Shmukler, Boris E and Topaloglu, Rezan and Hashmi, Seema and Hafeez, Farkhanda and Emma, Francesco and Greco, Marcella and Laube, Guido F and Fathy, Hanan M and Pohl, Martin and Gellermann, Jutta and Milosevic, Danko and Baum, Michelle A and Mane, Shrikant and Lifton, Richard P and Kane, Patricia M and Alper, Seth L and Hildebrandt, Friedhelm} } @article {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {516, title = {Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.}, journal = {J Am Soc Nephrol}, volume = {29}, year = {2018}, month = {2018 Sep}, pages = {2348-2361}, abstract = {

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{\textquoteright}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.

}, issn = {1533-3450}, doi = {10.1681/ASN.2017121265}, author = {van der Ven, Amelie T and Connaughton, Dervla M and Ityel, Hadas and Mann, Nina and Nakayama, Makiko and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Schulz, Julian and Braun, Daniela A and Schmidt, Johanna Magdalena and Schapiro, David and Schneider, Ronen and Warejko, Jillian K and Daga, Ankana and Majmundar, Amar J and Tan, Weizhen and Jobst-Schwan, Tilman and Hermle, Tobias and Widmeier, Eugen and Ashraf, Shazia and Amar, Ali and Hoogstraaten, Charlotte A and Hugo, Hannah and Kitzler, Thomas M and Kause, Franziska and Kolvenbach, Caroline M and Dai, Rufeng and Spaneas, Leslie and Amann, Kassaundra and Stein, Deborah R and Baum, Michelle A and Somers, Michael J G and Rodig, Nancy M and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Bogdanovic, Radovan and Staji{\'c}, Natasa and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan M and Milosevic, Danko and Al-Saffar, Muna and Awad, Hazem S and Eid, Loai A and Selvin, Aravind and Senguttuvan, Prabha and Sanna-Cherchi, Simone and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Wilson, Michael W and Mane, Shrikant M and Lifton, Richard P and Lee, Richard S and Bauer, Stuart B and Lu, Weining and Reutter, Heiko M and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} }