Genome-Wide Scanning Reveals Complex Etiology of Oculo-Auriculo-Vertebral Spectrum

Abstract

Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1 , which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.

Clinical and cytogenetic features of a Brazilian sample of patients with phenotype of oculo-auriculo-vertebral spectrum: a cross-sectional study

“…13 Th is reinforces the hypothesis that genetic heterogeneity and a variety of pathogenic mechanisms are contributory causes of this clinical entity, including epigenetic inheritance. 16 According to some authors, the VACTERL association and OAVS are a spectrum of anomalies derived from mesenchymal structures, probably caused by the same pathogenic mechanism.…”

Oculo-auriculo-vertebral spectrum: Clinical and molecular analysis of 51 patients

“…We also propose that the phenotype is affected by other genetic and non-genetic factors, in line with a oligogenic or even a multifactorial etiology [18]. It is seems clear to us that there are other genetic loci involved in OAVS and using a genome-wide exome or whole genome sequencing approach would be important to identify the gene(s) involved in its etiology.…”

“…Moreover, clinical studies have shown that, following careful history and clinical examination of the relatives of probands with OAVS, up to 45% of "unaffected" relatives do have minor OAVS manifestations [13]. Reports of familial cases following Mendelian inheritance [4,[14][15][16][17], as well as evidence for genetic linkage in two families [18,19], and the presence of OAVS features in patients with various chromosomal aberrations and genomic imbalances [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38], all suggest that some cases of OAVS have a genetic basis. Environmental causes have also been suggested, particularly twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes [1,3].…”

“…Characteristic clinical features of OAVS Patients with OAVS at different ages, presenting facial asymmetry/ hemifacial microsomia of different severities; and microtia and/or other ear anomalies. Map of OAVS loci Candidate genetic loci for OAVS that been suggested by the identification of chromosomal anomalies in patients with phenotypic characteristics of this spectrum (in red); by the identification of the breakpoints in apparently balanced chromosomal rearrangements (in green); by the presence of chromosomal mosaicism in individuals with OAVS features (in orange); by genome wide search forlinkage in families (in purple -full and, less convincingly due to a non-significant LOD score, in purple ---dashed); and by high density oligonucleotide array-CGH (blue)[2,7,8,[12][13][14][15][16][17][18][19][20][21][22]; chromosome 22…”

Hemifacial Microsomia with Spinal and Rib Anomalies: Prenatal Diagnosis and Postmortem Confirmation Using 3-D Computed Tomography Reconstruction

“…Although concordance has been reported for both monozygotic and dizygotic twins, the high level of discordance in monozygotic twins suggests that both genetic and environmental factors are involved [11,[17][18][19][20][21][22][23] . Currently, there is no specific causing gene that can be tested [24] .…”