Copy number variation analysis implicates novel pathways in patients with oculo‐auriculo‐vertebral‐spectrum and congenital heart defects
| Autor: | Maria Teresa Fadda, Sebastiano Bianca, Dario Cocciadiferro, Bruno Dallapiccola, Marina Goldoni, Maria Grazia Giuffrida, Bruno Marino, Silvana Briuglia, Marco Tartaglia, Leila B. Salehi, Valentina Guida, Francesca Forzano, Orazio Palumbo, Francesco Benedicenti, Francesco Pancheri, Franco Stanzial, Laura Bernardini, Daniela Melis, Marco Castori, Giorgio Iannetti, Teresa Mattina, Marianna Puzzo, Hossein Hozhabri, Chiara Barone, Massimo Carella, Carolina Putotto, Alessandro De Luca, Francesca Piceci Sparascio, Maria Cristina Digilio, Francesco Brancati, Mario Pagnoni, Ariana Kariminejad |
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| Rok vydání: | 2021 |
| Předmět: |
Heart Defects
Congenital Adult Male 0301 basic medicine Adolescent DNA Copy Number Variations 030105 genetics & heredity Biology Polymorphism Single Nucleotide Gene dosage Cohort Studies Congenital Young Adult 03 medical and health sciences Goldenhar Syndrome Gene duplication Genetics medicine Humans Copy-number variation Polymorphism Craniofacial Child Preschool copy-number-variants DACH1 DACH2 congenital heart disease Goldenhar syndrome oculo-auriculo-vertebral spectrum PAX-SIX-EYA-DACH network Gene Genetics (clinical) Heart Defects Genetic heterogeneity Microarray analysis techniques Infant Newborn Infant Single Nucleotide DACH1 Newborn Microarray Analysis medicine.disease DACH2 congenital heart disease Developmental disorder Child Preschool Female 030104 developmental biology |
| Zdroj: | Clinical Genetics. 100:268-279 |
| ISSN: | 1399-0004 0009-9163 |
| DOI: | 10.1111/cge.13994 |
| Popis: | Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait. |
| Databáze: | OpenAIRE |
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