@article {703, title = {COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Oct}, pages = {1105-1115}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45\%) that manifests before 30~years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4\% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

}, keywords = {Alleles, Amino Acid Substitution, Collagen Type IV, Computational Biology, Congenital Abnormalities, Databases, Genetic, DNA Mutational Analysis, Evolution, Molecular, Female, Genetic Association Studies, Genetic Loci, Genomics, Heterozygote, Humans, Kidney, Kidney Diseases, Cystic, Male, Mutation, Nephrotic Syndrome, Phenotype, Urinary Tract, Web Browser, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-02042-4}, author = {Kitzler, Thomas M and Schneider, Ronen and Kohl, Stefan and Kolvenbach, Caroline M and Connaughton, Dervla M and Dai, Rufeng and Mann, Nina and Nakayama, Makiko and Majmundar, Amar J and Wu, Chen-Han W and Kari, Jameela A and El Desoky, Sherif M and Senguttuvan, Prabha and Bogdanovic, Radovan and Staji{\'c}, Natasa and Valivullah, Zaheer and Lek, Monkol and Mane, Shrikant and Lifton, Richard P and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {630, title = {Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {13}, year = {2018}, month = {2018 01 06}, pages = {53-62}, abstract = {

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30\% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

RESULTS: In 74 of 300 families (25\%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7\%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38\% of consanguineous families and in 13\% of nonconsanguineous families, and 48\% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. , , , and were the most common genes in which we detected a mutation. In another 28\% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

}, issn = {1555-905X}, doi = {10.2215/CJN.04120417}, author = {Warejko, Jillian K and Tan, Weizhen and Daga, Ankana and Schapiro, David and Lawson, Jennifer A and Shril, Shirlee and Lovric, Svjetlana and Ashraf, Shazia and Rao, Jia and Hermle, Tobias and Jobst-Schwan, Tilman and Widmeier, Eugen and Majmundar, Amar J and Schneider, Ronen and Gee, Heon Yung and Schmidt, J Magdalena and Vivante, Asaf and van der Ven, Amelie T and Ityel, Hadas and Chen, Jing and Sadowski, Carolin E and Kohl, Stefan and Pabst, Werner L and Nakayama, Makiko and Somers, Michael J G and Rodig, Nancy M and Daouk, Ghaleb and Baum, Michelle and Stein, Deborah R and Ferguson, Michael A and Traum, Avram Z and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan and Zenker, Martin and Bakkaloglu, Sevcan A and M{\"u}ller, Dominik and Noyan, Aytul and Ozaltin, Fatih and Cadnapaphornchai, Melissa A and Hashmi, Seema and Hopcian, Jeffrey and Kopp, Jeffrey B and Benador, Nadine and Bockenhauer, Detlef and Bogdanovic, Radovan and Staji{\'c}, Natasa and Chernin, Gil and Ettenger, Robert and Fehrenbach, Henry and Kemper, Markus and Munarriz, Reyner Loza and Podracka, Ludmila and B{\"u}scher, Rainer and Serdaroglu, Erkin and Tasic, Velibor and Mane, Shrikant and Lifton, Richard P and Braun, Daniela 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} }