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

ABSTRACT: 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%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

SUBMITTER: Sanna-Cherchi S

PROVIDER: S-EPMC3516596 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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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:The application of genome sequencing in patients with intellectual disability and congenital anomalies (ID/CA) typically identifies causative mutations only in a minority of cases. We hypothesized that some cases of ID/CA are caused by epigenetic aberrations that dysregulate normal genome function, and that these would be missed by conventional sequencing approaches. We performed Illumina 450k DNA methylation profiling in ~500 individuals with ID/CA, who were negative for causative mutations by microarray, exome- and/or whole genome sequencing. We screened patient methylation profiles for epimutations absent in ~1,500 controls, and validated these by bisulfite sequencing, revealing that epimutations represent large methylation changes specifically on one allele. Parental studies show that approximately half represent de novo events, a rate significantly higher than that seen in controls. We identified seven recurrent events, two of which (FMR1, MEG3) have known disease associations, validating our method for detecting pathogenic epimutations. From large-scale sequencing, population and expression studies we conclude that epimutations are: (i) Frequently associated with extreme outlier and mono-allelic gene expression, with an impact comparable to loss-of-function mutations; (ii) Generally conserved across multiple tissues within an individual, validating the use of blood DNA to study ID/CA; (iii) Can occur secondary to cis-linked regulatory mutations, providing a rationale for interpreting non-coding genetic variants; (iv) Occur sporadically with a remarkably high de novo rate, and (v) Exhibit non-Mendelian inheritance, likely being reset between generations by epigenetic reprogramming during embryogenesis. We conclude that epimutations underlie 5-10% of patients with ID/CA who are refractory to conventional mutation screening, and propose that epigenome profiling represents a promising method for the study of human disease that complements sequence-based approaches.

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

Publications

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

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