The emerging role of genomics in the diagnosis and workup of congenital urinary tract defects: a novel deletion syndrome on chromosome 3q13.31-22.1.

backgroundCopy number variants (CNVs) are increasingly recognized as an important cause of congenital malformations and likely explain over 16% of cases of congenital anomalies of the kidney and urinary tract (CAKUT). Here, we illustrate how a molecular diagnosis of CNV can be beneficial to the clinical management of a pediatric patient presenting with CAKUT and other organ defects.

methodsWe describe a 14-year-old girl with a large de novo deletion of chromosome 3q13.31-22.1 that disrupts 101 known genes. The patient presented with CAKUT, neurodevelopmental delay, agenesis of corpus callosum (ACC), cardiac malformations, electrolyte and endocrine disorders, skeletal abnormalities and dysmorphic features. We performed extensive annotation of the deleted region to prioritize genes for specific phenotypes and to predict future disease risk.

resultsOur case defined new minimal chromosomal candidate regions for both CAKUT and ACC. The presence of the CASR gene in the deleted interval predicted a diagnosis of hypocalciuric hypercalcemia, which was confirmed by the serum and urine chemistries. Our gene annotation explained clinical hypothyroidism and predicted that the index case is at increased risk of thoracic aortic aneurysm, renal cell carcinoma and myeloproliferative disorder.

conclusionsExtended annotation of CNV regions refines the diagnosis and uncovers previously unrecognized phenotypic features. This approach enables personalized treatment and prevention strategies in patients harboring genomic deletions.