Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects

被引：11

作者：

Guida, Valentina ^{[1
]}

Sparascio, Francesca Piceci ^{[1
,2
]}

Bernardini, Laura ^{[1
]}

Pancheri, Francesco ^{[3
]}

Melis, Daniela ^{[4
,5
]}

Cocciadiferro, Dario ^{[1
,6
]}

Pagnoni, Mario ^{[7
]}

Puzzo, Marianna ^{[1
]}

Goldoni, Marina ^{[1
]}

Barone, Chiara ^{[8
]}

Hozhabri, Hossein ^{[1
]}

Putotto, Carolina ^{[3
]}

Giuffrida, Maria Grazia ^{[1
]}

Briuglia, Silvana ^{[9
]}

Palumbo, Orazio ^{[1
]}

Bianca, Sebastiano ^{[8
]}

Stanzial, Franco ^{[10
]}

Benedicenti, Francesco ^{[10
]}

Kariminejad, Ariana ^{[11
]}

Forzano, Francesca ^{[12
]}

Salehi, Leila Baghernajad ^{[13
]}

Mattina, Teresa ^{[14
]}

Brancati, Francesco ^{[15
]}

Castori, Marco ^{[1
]}

Carella, Massimo ^{[1
]}

Fadda, Maria Teresa ^{[7
]}

Iannetti, Giorgio ^{[7
]}

Dallapiccola, Bruno ^{[16
]}

Digilio, Maria Cristina ^{[16
]}

Marino, Bruno ^{[3
]}

Tartaglia, Marco ^{[16
]}

De Luca, Alessandro ^{[1
]}

机构：

[1] Fdn IRCCS Casa Sollievo Sofferenza, Med Genet Div, San Giovanni Rotondo, Italy

[2] Sapienza Univ Rome, Dept Expt Med, Rome, Italy

[3] Sapienza Univ Rome, Dept Pediat Obstet & Gynecol, Rome, Italy

[4] Univ Naples Federico II, Dept Translat Med Sci, Sect Pediat, Naples, Italy

[5] Univ Salerno, Scuola Med Salernitana, Dept Med Surg & Dent, Salerno, Italy

[6] Bambino Gesu Pediat Hosp, Translat Cytogen Res Unit, IRCCS, Rome, Italy

[7] Policlin Umberto 1, Dept Maxillofacial Surg, Rome, Italy

[8] ARNAS Garibaldi, Referral Ctr Rare Genet Dis, Med Genet, Catania, Italy

[9] Univ Messina, Dept Human Pathol Adult & Childhood Gaetano Barre, Unit Emergency Pediat, Messina, Italy

[10] Reg Hosp Bolzano, Dept Pediat, Genet Counseling Serv, Bolzano, Italy

[11] Kariminejad Najmabadi Pathol & Genet Ctr, Tehran, Iran

[12] Guys & St Thomas NHS Fdn Trust, Clin Genet Dept, London, England

[13] Tor Vergata Univ Hosp, Med Genet Unit, PTV, Rome, Italy

[14] Univ Catania, Unit Med Genet, Catania, Italy

[15] Univ Aquila, Unit Med Genet, Dept Life Hlth & Environm Sci, Laquila, Italy

[16] Osped Pediatr Bambino Gesu, IRCCS, Genet & Rare Dis Res Div, Rome, Italy

来源：

CLINICAL GENETICS | 2021年 / 100卷 / 03期

关键词：

copy‐ number‐ variants; DACH1; DACH2; congenital heart disease; Goldenhar syndrome; PAX‐ SIX‐ EYA‐ DACH network; oculo‐ auriculo‐ vertebral spectrum; OCULOAURICULOVERTEBRAL DYSPLASIA; FUNCTIONAL-ANALYSIS; CARDIAC DEFECTS; MALFORMATION; VARIANTS; GENES; OTX2; ABNORMALITIES; ASSOCIATION; MUTATIONS;

D O I：

10.1111/cge.13994

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：268 / 279

页数：12

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