Dataset Information

Copy Number Variation in Congenital Kidney Malformations

ABSTRACT:

We report a study of large rare, copy number variants (CNVs) in 192 patients with renal hypodysplasia (RHD). Congenital malformations of the kidney and urinary tract are present in 3 to 7 per 1,000 births, accounting for 16% of birth defects. These malformations account for 40-50% of pediatric and 7% of adult end-stage renal disease worldwide. Among these malformations, RHD represents a severe forms of disease with profound impact on long-term renal survival. We found that a significant fraction of RHD patients have a molecular diagnosis attributable to a genomic disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances.

PROVIDER: phs000565.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Copy-number disorders are a common cause of congenital kidney malformations.

Sanna-Cherchi Simone S Kiryluk Krzysztof K Burgess Katelyn E KE Bodria Monica M Sampson Matthew G MG Hadley Dexter D Nees Shannon N SN Verbitsky Miguel M Perry Brittany J BJ Sterken Roel R Lozanovski Vladimir J VJ Materna-Kiryluk Anna A Barlassina Cristina C Kini Akshata A Corbani Valentina V Carrea Alba A Somenzi Danio D Murtas Corrado C Ristoska-Bojkovska Nadica N Izzi Claudia C Bianco Beatrice B Zaniew Marcin M Flogelova Hana H Weng Patricia L PL Kacak Nilgun N Giberti Stefania S Gigante Maddalena M Arapovic Adela A Drnasin Kristina K Caridi Gianluca G Curioni Simona S Allegri Franca F Ammenti Anita A Ferretti Stefania S Goj Vinicio V Bernardo Luca L Jobanputra Vaidehi V Chung Wendy K WK Lifton Richard P RP Sanders Stephan S State Matthew M Clark Lorraine N LN Saraga Marijan M Padmanabhan Sandosh S Dominiczak Anna F AF Foroud Tatiana T Gesualdo Loreto L Gucev Zoran Z Allegri Landino L Latos-Bielenska Anna A Cusi Daniele D Scolari Francesco F Tasic Velibor V Hakonarson Hakon H Ghiggeri Gian Marco GM Gharavi Ali G AG

American journal of human genetics 20121115 6

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) R ...[more]

PMID: 23159250

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Project description:<p>Primary vesicoureteric reflux (PVUR), or non-syndromic VUR, is the most common type of congenital anomaly of the kidney and the urinary tract (CAKUT). PVUR is the single most important risk factor for pyelonephritis and renal parenchymal scarring in the pediatric age group. Renal parenchymal scarring due to PVUR is referred to as reflux nephropathy and is a major cause of end stage kidney disease requiring dialysis and kidney transplantation in children. PVUR shows familial aggregation; however, the specific genetic cause(s) of PVUR is unknown despite a number of linkage studies. Reasons for this include: variable expression of the disease, difficulty with case ascertainment, genetic heterogeneity and lack of large pedigrees that can facilitate locus identification. We have ascertained a large 97 member PVUR kindred spanning five generations. We performed a genome-wide linkage study (GWLS) on this family and obtained a significant genome-wide LOD score of 3.3 on chromosome 6p. We performed exome sequencing on affected individuals in the family and identified mutations in tenascin XB (TNXB) as a cause of familial VUR. The proposed studies have the following specific objectives: a) to define the role of tenascin genes in the etiology of PVUR, and b) to identify new PVUR causative genes. Our specific aims are (1) To perform mutation analysis in TNXB and other tenascins in a cohort of 200 individuals with familial and sporadic PVUR and define genotype/phenotype correlations. (2) To perform sequential genome wide linkage studies (GWLS) and whole exome/targeted sequencing in families with PVUR. Impact on public health: Identification of PVUR genes may provide a novel non-invasive diagnostic tool for a subset of children with PVUR. Furthermore, this research will provide insights into the pathogenesis of PVUR and further elucidate the pathways involved in the development of the kidney and genitourinary tract. Future studies will define the role of the genes in the etiology of other malformations of the kidney and urinary tract and also seek to unravel the mechanisms by which the identified gene causes PVUR and other malformations of the kidney and the urinary tract.</p>

Dataset Information

Copy Number Variation in Congenital Kidney Malformations

Publications

Copy-number disorders are a common cause of congenital kidney malformations.

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