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

Abstract

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.

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

“…Interestingly, EYA1 , SIX1 and SIX5 are associated with overlapping syndromes (table 3). Moreover, a DACH1 deletion and a DACH2 duplication were recently described in two independent patients with OAVS 57. Taken together, these data support that deregulation of PAX-SIX-EYA-DACH signalling pathway would be a consistent hypothesis for the physiopathology of OAVS.…”

“…Six independent studies were performed analysing patients with OAVS by CMA in order to identify CNVs 10 13 28 45 57 99. Only two studies described cohorts of significant size: our team first published an analysis of 86 patients with OAVS, identifying 12.8% of CNVs,10 while the second cohort of 72 patients found 18% of pathogenic or possibly pathogenic CNVs 45.…”

Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome

“…There is an increasing number of reported genes associated with OAVS, as well as putative risk alleles from GWA studies [ 19 ]. A common theme occurring is the involvement of the PSED network, for example, a recurrent missense variant occurring in EYA3 or intragenic genomic alterations of DACH1 or DACH2 [ 10 , 20 ]. All of these are predicted to act through a dominant genetic mechanism, as opposed to the biallelic loss of function mechanism for PAX1 in OTFCS2.…”

Investigation of Genetic Causes in a Developmental Disorder: Oculoauriculovertebral Spectrum

“…Frequency of congenital heart defects in OAVS varies vastly between different studies, ranging between 5% and 58% (Guida et al, 2021). The reason for the high heterogeneity between different OAVS cohorts is yet to be clarified.…”