Rare single‐nucleotide variants in oculo‐auriculo‐vertebral spectrum (OAVS)

Abstract

BackgroundOculo‐auriculo‐vertebral spectrum (OAVS) is a craniofacial developmental disorder that affects structures derived from the first and second pharyngeal arches. The clinically heterogeneous phenotype involves mandibular, oral, and ear development anomalies. Etiology is complex and poorly understood. Genetic factors have been associated, evidenced by chromosomal abnormalities affecting different genomic regions and genes. However, known pathogenic single‐nucleotide variants (SNVs) have only been identified in MYT1 in a restricted number of patients. Therefore, investigations of SNVs on candidate genes may reveal other pathogenic mechanisms. MethodsIn a cohort of 73 patients, coding and untranslated regions (UTR) of 10 candidate genes (CRKL, YPEL1, MAPK1, NKX3‐2, HMX1, MYT1, OTX2, GSC, PUF60, HOXA2) were sequenced. Rare SNVs were selected and in silico predictions were performed to ascertain pathogenicity. Likely pathogenic variants were validated by Sanger sequencing and heritability was assessed when possible.ResultsFour likely pathogenic variants in heterozygous state were identified in different patients. Two SNVs were located in the 5’UTR of YPEL1; one in the 3’UTR of CRKL and one in the 3’UTR of OTX2.ConclusionOur work described variants in candidate genes for OAVS and supported the genetic heterogeneity of the spectrum.

Novel MYT1 variants expose the complexity of oculo‐auriculo‐vertebral spectrum genetic mechanisms

“…No clinical conditions have been associated with this variant thus far. None of the five patients presented rare SNVs or likely pathogenic or pathogenic CNVs previously studied (Bragagnolo et al, 2018; Zamariolli et al, 2019), reinforcing that this variant could play a role in the development of the disease in these patients. Although common features are observed between the five patients who carried this SNV, there is no consistency among them for many of the phenotypic characteristics observed (Table 2).…”

“…Filtered SNVs were annotated using the WGSA annotation pipeline (v0.85; Liu et al, 2016) and functional relevance was ascertained based on prediction from in silico tools as described in Zamariolli et al (2019). Briefly, SNVs were considered likely deleterious when simultaneously predicted as deleterious by four queried algorithms for non‐synonymous variants (SIFT, Polyphen‐2, FATHMM‐XF, and Mutation Taster) and two algorithms for synonymous variants (FATHMM‐XF, and Mutation Taster).…”

“…Briefly, SNVs were considered likely deleterious when simultaneously predicted as deleterious by four queried algorithms for non‐synonymous variants (SIFT, Polyphen‐2, FATHMM‐XF, and Mutation Taster) and two algorithms for synonymous variants (FATHMM‐XF, and Mutation Taster). The ones classified as such were then validated by Sanger sequencing as previously described (Zamariolli et al, 2019). Variants were also assessed in patients' parents when DNA samples were available.…”

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS)

“…We then performed a literature-based gene prioritization: first, we screened our gene-associated deregulations by intersecting the gene lists with those confirmed or candidates to be causative of OAVS that emerged from both genetic (exome sequencing) or cytogenetic (SNP-array) studies. No epigenetic deregulations were found to be associated to MYT1 gene [ 22 , 23 ] or others proposed loci including ZYG11B [ 25 ], AMIGO2 [ 24 ], OTX2 / YPEL1 / CRKL [ 21 , 37 ], and NKX3-2 ( BAPX1 ) [ 29 ]. The only positive matching was found for the gene Xyloside Xylosyltransferase1 ( XXYLT1 ) localized in a region previously reported for a de novo microduplication on chromosome 3 (3q29) in an OAVS patient [ 38 ].…”

Candidate genes of oculo‐auriculo‐vertebral spectrum in 22q region: A systematic review

“…In addition, maternal allele variants of YPEL1 , when with incomplete penetration trait associated with genetic and/or environmental factors, could lead to OAVS phenotype. Clinical features have not been associated with neither MAPK1 nor YPEL1 (Zamariolli et al, 2019). Within the cases included in our review, both genes were always simultaneously deleted when cited (dos Santos et al, 2014; Spineli‐Silva et al, 2018; Xu et al, 2008).…”