Genetic lesions in a series of russian CAKUT patients: a pilot study

Congenital Anomalies of Kidney and Urinary Tract (CAKUT) are a frequent cause of chronic kidney disease in children and young adults. Anomalies of the CAKUT spectrum are often associated with monogenic conditions and occur both as isolated malformations and in the structure of hereditary syndromes. CAKUT is characterized by marked genetic heterogeneity, incomplete penetrance, and variability of phenotypic manifestations. Objective: to assess the spectrum of inherited genetic defects in a cohort of Russian CAKUT patients, to trace genotype/phenotype correlations. Materials and methods: patients with CAKUT-related chronic kidney disease (5 isolated and 11 syndromal cases) underwent clinical exome sequencing; when analyzing the results, priority was given to the search for rare variants in genes associated with the development of CAKUT (n=91), as well as cystic renal dysplasia/nephronophthisis (n=72). Results: Probable cause of the disease was identified in 7 of 16 patients (44%): EYA1, PAX2, MAFB, KMT2D, GATA3, and TMEM67 mutations were detected. All pathogenic/likely pathogenic variants were identified in syndromal CAKUT varieties only (branchio-oto-renal and coloboma-renal syndromes, multicentric carpotarsal osteolysis, Kabuki and Barakat syndromes, nephronophthisis type 11). One patient was found to harbor rare missense BNC2, NOTCH2, and KMT2D variants of unknown clinical significance. Except autosomal recessive nephronophthisis 11, all identified inherited diseases had an autosomal dominant type of inheritance, with at least 3/6 (50%) of cases being caused by de novo mutations. Interestingly, nephronophthisis, presenting as renal hypodysplasia, demonstrated the absence of cysts and was clinically recognized as CAKUT syndrome. Conclusion: identification of the genetic (monogenic) nature of the disease opens up opportunities for medical and genetic counseling of families and clarification of prognosis, as well as allows timely detection of the possible extrarenal manifestations.

CAKUT, врожденные пороки развития почек и мочевыводящих путей, мутации, высокопроизводительное секвенирование, CAKUT, Congenital Anomalies of Kidney and Urinary Tract, mutations, next-generation sequencing

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