DETECTION OF COPY NUMBER VARIATIONS BY SINGLE-NUCLEOTIDE-POLYMORPHISM ARRAY IN PATIENTS WITH END-STAGE RENAL DISEASE OF UNKNOWN ETIOLOGY

Abstract BACKGROUND AND AIMS Establishing the genetic basis of renal disease is pivotal to improve diagnostic and treatment strategies. Pathogenic copy number variations (CNVs) caused by chromosomal imbalances contribute significantly to the pediatric renal disease burden, especially in children with congenital anomalies of the kidney and urinary tract (CAKUT). The role of CNVs in chronic kidney disease of unknown etiology (uCKD) is scarcely investigated, although this group comprises about 20% of adults with end-stage renal disease (ESRD). We screened for causal CNVs in a preliminary sample of patients with ESRD from unknown etiology. METHOD We recruited 94 patients registered with ESRD ≤age 50 from uCKD or hypertension from the Danish Nephrology Registry. Medical records and previous kidney biopsies were initially reviewed, and patients were excluded if a specific cause of kidney disease other than hypertension was identified (n = 35). We performed genome-wide single-nucleotide-polymorphism (SNP) array in 59 patients to identify copy number gains and losses. All CNVs were systematically evaluated as possible causes of kidney disease and broadly classified into three main categories: ‘Normal’, ‘Pathogenic’ or ‘Variant of uncertain significance.’ RESULTS The SNP array results were normal in 57 patients (96.6%). In the remaining two patients (3.4%), we detected pathogenic CNVs with incomplete penetrance in hot spot loci associated with CAKUT: One male patient with ESRD at age 18 was a heterozygous carrier of a 545 kb microdeletion on chromosome 16p11.2 (29.63 Mb to 30.18 Mb). He had left-side renal agenesis and a hypoplastic right kidney at presentation, but no history of developmental delay or dysmorphic features. The microdeletion was considered likely causal, because it included the CAKUT driver gene TBX6 similar to other heterozygous carriers of 16p11.2 microdeletions with isolated renal agenesis or dysplasia. A second patient with ESRD at age 49 had 3.66 Mb duplication on chromosome 1q21.1 (145.43 Mb to 149.09 Mb) in heterozygous form. The patient had no reported CAKUT or other features associated with CNVs in the 1q21.1 loci, and the duplication was therefore deemed unrelated to his renal disease. CONCLUSION Disease-causing CNVs are not frequent in this limited sample of patients with ESRD from unknown etiology. CNV analysis by SNP-array may be most effective in patients with uCKD combined with CAKUT features.