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

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

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)987-997
Number of pages11
JournalAmerican Journal of Human Genetics
Volume91
Issue number6
DOIs
StatePublished - Dec 7 2012

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Kidney
Population Control
Gene Dosage
Urinary Tract
Databases
Population
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Sanna-Cherchi, S., Kiryluk, K., Burgess, K. E., Bodria, M., Sampson, M. G., Hadley, D., ... Gharavi, A. G. (2012). Copy-number disorders are a common cause of congenital kidney malformations. American Journal of Human Genetics, 91(6), 987-997. https://doi.org/10.1016/j.ajhg.2012.10.007

Copy-number disorders are a common cause of congenital kidney malformations. / Sanna-Cherchi, Simone; Kiryluk, Krzysztof; Burgess, Katelyn E.; Bodria, Monica; Sampson, Matthew G.; Hadley, Dexter; Nees, Shannon N.; Verbitsky, Miguel; Perry, Brittany J.; Sterken, Roel; Lozanovski, Vladimir J.; Materna-Kiryluk, Anna; Barlassina, Cristina; Kini, Akshata; Corbani, Valentina; Carrea, Alba; Somenzi, Danio; Murtas, Corrado; Ristoska-Bojkovska, Nadica; Izzi, Claudia; Bianco, Beatrice; Zaniew, Marcin; Flogelova, Hana; Weng, Patricia L.; Kacak, Nilgun; Giberti, Stefania; Gigante, Maddalena; Arapovic, Adela; Drnasin, Kristina; Caridi, Gianluca; Curioni, Simona; Allegri, Franca; Ammenti, Anita; Ferretti, Stefania; Goj, Vinicio; Bernardo, Luca; Jobanputra, Vaidehi; Chung, Wendy K.; Lifton, Richard P.; Sanders, Stephan; State, Matthew; Clark, Lorraine N.; Saraga, Marijan; Padmanabhan, Sandosh; Dominiczak, Anna F.; Foroud, Tatiana; Gesualdo, Loreto; Gucev, Zoran; Allegri, Landino; Latos-Bielenska, Anna; Cusi, Daniele; Scolari, Francesco; Tasic, Velibor; Hakonarson, Hakon; Ghiggeri, Gian Marco; Gharavi, Ali G.

In: American Journal of Human Genetics, Vol. 91, No. 6, 07.12.2012, p. 987-997.

Research output: Contribution to journalArticle

Sanna-Cherchi, S, Kiryluk, K, Burgess, KE, Bodria, M, Sampson, MG, Hadley, D, Nees, SN, Verbitsky, M, Perry, BJ, Sterken, R, Lozanovski, VJ, Materna-Kiryluk, A, Barlassina, C, Kini, A, Corbani, V, Carrea, A, Somenzi, D, Murtas, C, Ristoska-Bojkovska, N, Izzi, C, Bianco, B, Zaniew, M, Flogelova, H, Weng, PL, Kacak, N, Giberti, S, Gigante, M, Arapovic, A, Drnasin, K, Caridi, G, Curioni, S, Allegri, F, Ammenti, A, Ferretti, S, Goj, V, Bernardo, L, Jobanputra, V, Chung, WK, Lifton, RP, Sanders, S, State, M, Clark, LN, Saraga, M, Padmanabhan, S, Dominiczak, AF, Foroud, T, Gesualdo, L, Gucev, Z, Allegri, L, Latos-Bielenska, A, Cusi, D, Scolari, F, Tasic, V, Hakonarson, H, Ghiggeri, GM & Gharavi, AG 2012, 'Copy-number disorders are a common cause of congenital kidney malformations', American Journal of Human Genetics, vol. 91, no. 6, pp. 987-997. https://doi.org/10.1016/j.ajhg.2012.10.007
Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D et al. Copy-number disorders are a common cause of congenital kidney malformations. American Journal of Human Genetics. 2012 Dec 7;91(6):987-997. https://doi.org/10.1016/j.ajhg.2012.10.007
Sanna-Cherchi, Simone ; Kiryluk, Krzysztof ; Burgess, Katelyn E. ; Bodria, Monica ; Sampson, Matthew G. ; Hadley, Dexter ; Nees, Shannon N. ; Verbitsky, Miguel ; Perry, Brittany J. ; Sterken, Roel ; Lozanovski, Vladimir J. ; Materna-Kiryluk, Anna ; Barlassina, Cristina ; Kini, Akshata ; Corbani, Valentina ; Carrea, Alba ; Somenzi, Danio ; Murtas, Corrado ; Ristoska-Bojkovska, Nadica ; Izzi, Claudia ; Bianco, Beatrice ; Zaniew, Marcin ; Flogelova, Hana ; Weng, Patricia L. ; Kacak, Nilgun ; Giberti, Stefania ; Gigante, Maddalena ; Arapovic, Adela ; Drnasin, Kristina ; Caridi, Gianluca ; Curioni, Simona ; Allegri, Franca ; Ammenti, Anita ; Ferretti, Stefania ; Goj, Vinicio ; Bernardo, Luca ; Jobanputra, Vaidehi ; Chung, Wendy K. ; Lifton, Richard P. ; Sanders, Stephan ; State, Matthew ; Clark, Lorraine N. ; Saraga, Marijan ; Padmanabhan, Sandosh ; Dominiczak, Anna F. ; Foroud, Tatiana ; Gesualdo, Loreto ; Gucev, Zoran ; Allegri, Landino ; Latos-Bielenska, Anna ; Cusi, Daniele ; Scolari, Francesco ; Tasic, Velibor ; Hakonarson, Hakon ; Ghiggeri, Gian Marco ; Gharavi, Ali G. / Copy-number disorders are a common cause of congenital kidney malformations. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 6. pp. 987-997.
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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.",
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T1 - Copy-number disorders are a common cause of congenital kidney malformations

AU - Sanna-Cherchi, Simone

AU - Kiryluk, Krzysztof

AU - Burgess, Katelyn E.

AU - Bodria, Monica

AU - Sampson, Matthew G.

AU - Hadley, Dexter

AU - Nees, Shannon N.

AU - Verbitsky, Miguel

AU - Perry, Brittany J.

AU - Sterken, Roel

AU - Lozanovski, Vladimir J.

AU - Materna-Kiryluk, Anna

AU - Barlassina, Cristina

AU - Kini, Akshata

AU - Corbani, Valentina

AU - Carrea, Alba

AU - Somenzi, Danio

AU - Murtas, Corrado

AU - Ristoska-Bojkovska, Nadica

AU - Izzi, Claudia

AU - Bianco, Beatrice

AU - Zaniew, Marcin

AU - Flogelova, Hana

AU - Weng, Patricia L.

AU - Kacak, Nilgun

AU - Giberti, Stefania

AU - Gigante, Maddalena

AU - Arapovic, Adela

AU - Drnasin, Kristina

AU - Caridi, Gianluca

AU - Curioni, Simona

AU - Allegri, Franca

AU - Ammenti, Anita

AU - Ferretti, Stefania

AU - Goj, Vinicio

AU - Bernardo, Luca

AU - Jobanputra, Vaidehi

AU - Chung, Wendy K.

AU - Lifton, Richard P.

AU - Sanders, Stephan

AU - State, Matthew

AU - Clark, Lorraine N.

AU - Saraga, Marijan

AU - Padmanabhan, Sandosh

AU - Dominiczak, Anna F.

AU - Foroud, Tatiana

AU - Gesualdo, Loreto

AU - Gucev, Zoran

AU - Allegri, Landino

AU - Latos-Bielenska, Anna

AU - Cusi, Daniele

AU - Scolari, Francesco

AU - Tasic, Velibor

AU - Hakonarson, Hakon

AU - Ghiggeri, Gian Marco

AU - Gharavi, Ali G.

PY - 2012/12/7

Y1 - 2012/12/7

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AB - 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.

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