Background: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). Aims: Identification of genomic disorders in DD/ID. Materials and methods: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. Results: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. Discussion and conclusion: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes

DI GREGORIO, ELEONORA;RIBERI, EVELISE;BELLIGNI, ELGA FABIA;BIAMINO, ELISA;ALA, UGO;CALCIA, ALESSANDRO;BAGNASCO, Irene;Carli, Diana;GAI, GIORGIA;KELLER, ROBERTO;MANDRILE, Giorgia;NARETTO, VALERIA GIORGIA;SIRCHIA, Fabio;SORASIO, LORENA;ZONTA, Andrea;CAVALIERI, Simona;GIORGIO, ELISA;MANCINI, CECILIA;FERRERO, MARTA;BRUSSINO, Alessandro;GANDIONE, Marina;GIACHINO, Daniela Francesca;DE MARCHI, Mario;restagno, gabriella;PROVERO, Paolo;PASINI, Barbara;BRUSCO, Alfredo;FERRERO, Giovanni Battista
Last
2017-01-01

Abstract

Background: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). Aims: Identification of genomic disorders in DD/ID. Materials and methods: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. Results: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. Discussion and conclusion: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.
2017
92
4
415
422
http://onlinelibrary.wiley.com/doi/10.1111/cge.13009/epdf
CNV; array-CGH; autism spectrum disorder; developmental delay; genomic disorders; intellectual disability
DI GREGORIO, Eleonora; Riberi, Evelise; Belligni, ELGA FABIA; Biamino, Elisa; Spielmann, Malte; Ala, Ugo; Calcia, Alessandro; Bagnasco, Irene; Carli, ...espandi
File in questo prodotto:
File Dimensione Formato  
112. array-CGH global_ Clinical_Genetics 2017.pdf

Accesso riservato

Descrizione: File principale
Tipo di file: PDF EDITORIALE
Dimensione 1.37 MB
Formato Adobe PDF
1.37 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
CNV_preprint.pdf

Open Access dal 08/11/2018

Descrizione: postprint
Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 2.51 MB
Formato Adobe PDF
2.51 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1631611
Citazioni
  • ???jsp.display-item.citation.pmc??? 26
  • Scopus 44
  • ???jsp.display-item.citation.isi??? 40
social impact