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

Abstract

Background Copy number variants (CNVs) are increasingly recognized as an important cause of congenital malformations and likely explain over 16% cases of CAKUT. Here, we illustrate how a molecular diagnosis of CNV can inform the clinical management of a pediatric patient presenting with CAKUT and other organ defects. Methods We describe a 14 year-old girl with a large de novo deletion of chromosome 3q13.31-22.1 that disrupts 101 known genes and manifests with CAKUT, neurodevelopmental delay, agenesis of corpus callosum (ACC), cardiac malformations, electrolyte and endocrine disorders, skeletal abnormalities and dysmorphic features. We perform extensive annotation of the deleted region to prioritize genes for specific phenotypes and to predict future disease risk. Results Our case defined new minimal chromosomal candidate regions for both CAKUT and ACC. Moreover, the presence of the CASR gene in the deleted interval predicted a diagnosis of hypocalciuric hypercalcemia, which was confirmed by 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. Conclusions Extended annotation of CNV regions refines diagnosis and uncovers previously unrecognized phenotypic features. This approach enables personalized treatment and prevention strategies in patients harboring genomic deletions.

Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney

“…We recently reported on the potential for functional interpretation of genes underlying large pathogenic CNVs using quantitative-PCR validation, extensive literature and database searches to improve the diagnostic workup of a patient with a complex developmental phenotype comprising CAKUT, intellectual disability, limb defects, and other anomalies. 15 , 43 Here we propose an original pipeline to facilitate identification of high-priority genetic drivers for CNVs. This approach may be useful to narrow down the list of genes for follow-up resequencing studies and functional modeling in genetically engineered animal systems.…”

Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia

“…Thus, we only identified one copy number variation in 56 patients (2%) with calcium metabolism disorders using the MLPA technique (data not published). Moreover, a previous study did not identify any copy number variation in a large cohort of 257 patient samples using MLPA ( 9 , 10 ). In our laboratory, firstly, the exons and flanking intronic sequences of the CASR gene are screened for mutations by PCR followed by direct sequencing, and secondly, when the results are negative, the MLPA is performed.…”

“…The second deletion consisted in a large deletion of chromosome 3p13.31-22.1 that included 101 known genes, including the CASR gene. The individual presented multiple disorders, including hypercalcemia and hypocalciuria ( 9 ).…”

Integrated small copy number variations and epigenome maps of disorders of sex development

“…Large CNVs detected by CMA from cohorts of patients with similar phenotypic findings have been aligned to identify small regions of overlap that contain candidate genes. 2 , 40 , 43–46 Data from genome sequencing have also been utilized to identify small CNVs. 9 , 10 , 47 , 48 These studies have further demonstrated that, regardless of size, the clinical relevance of the detected CNV is determined by gene content and other layers of evidence.…”