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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

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Abstract

Background

Copy 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.

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. 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.

Results

Our 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.

Conclusions

Extended 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.

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Acknowledgments

We are grateful to the devoted family of the index case for their ongoing participation. This study is the result of scientific collaboration between the Department of Medical Genetics, Poznan University of Medical Sciences in Poland and the Division of Nephrology at Columbia University in New York, USA. Our funding sources include: A.M.K., A.L.B., and The Polish Registry of Congenital Malformations (PRCM) are supported by the Polish Ministry of Health; A.G.G. and K.K. are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK080099 and K23-DK090207, respectively. S.S.C. is supported by the American Heart Association Grant in Aid 13GRNT14680075 and by the American Society of Nephrology Carl W Gottschalk Research Scholar Grant.

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Authors and Affiliations

  1. Department of Medical Genetics, Poznan University of Medical Sciences, Grunwaldzka 55/15, 60-352, Poznan, Poland

    Anna Materna-Kiryluk & Anna Latos-Bielenska

  2. Polish Registry of Congenital Malformations (PRCM), Poznan, Poland

    Anna Materna-Kiryluk & Anna Latos-Bielenska

  3. Center for Medical Genetics GENESIS, Poznan, Poland

    Anna Materna-Kiryluk & Anna Latos-Bielenska

  4. Division of Nephrology, Department of Medicine, Columbia University, 1150 St Nicholas Ave, Russ Berrie Pavilion #413, New York, NY, 10032, USA

    Krzysztof Kiryluk, Katelyn E. Burgess, Simone Sanna-Cherchi & Ali G. Gharavi

  5. Department of Pediatrics, Goleniów Hospital Medical Center, Goleniów, Poland

    Arkadiusz Bieleninik

  6. Department of Medicine, St. Luke’s-Roosevelt Hospital Center, New York, NY, USA

    Simone Sanna-Cherchi

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  1. Anna Materna-Kiryluk
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Correspondence to Anna Materna-Kiryluk or Krzysztof Kiryluk.

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Anna Materna-Kiryluk and Krzysztof Kiryluk contributed equally to this work.

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Electronic Supplementary Material Dataset 1

Reference genes in the minimal candidate regions for CAKUT and ACC. Column legend: chromosome, transcript start (bp, hg-18), transcript stop (bp, hg-18), gene name, predicted probability of haploinsufficiency according to the probabilistic model of Huang et al. [15], membership in the minimal candidate region for CAKUT and ACC (TXT 3 kb)

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Materna-Kiryluk, A., Kiryluk, K., Burgess, K.E. et al. 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. Pediatr Nephrol 29, 257–267 (2014). https://doi.org/10.1007/s00467-013-2625-2

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