Investigation of Genetic Causes in a Developmental Disorder: Oculoauriculovertebral Spectrum

Abstract

Objective Oculoauriculovertebral spectrum (OAVS) is a genetically and clinically heterogeneous disorder that occurs due to a developmental field defect of the first and second pharyngeal arches. Even though recent whole exome sequencing studies (WES) have led to identification of several genes associated with this spectrum in a subset of individuals, complete pathogenesis of OAVS remains unsolved. In this study, molecular genetic etiology of OAVS was systematically investigated. Design/Setting/Patients A cohort of 23 Turkish patients with OAVS, referred to Hacettepe University Hospital, Department of Pediatric Genetics from 2008 to 2018, was included in this study. Minimal diagnostic criteria for OAVS were considered as unilateral microtia or hemifacial microsomia with preauricular skin tag. The cohort was clinically reevaluated for craniofacial and extracranial findings. Molecular etiology was investigated using candidate gene sequencing following copy number variant (CNV) analysis. WES was also performed for 2 of the selected patients. Results Patients in the study cohort presented similar demographic and phenotypic characteristics to previously described patients in the literature except for a higher frequency of bilaterality, cardiac findings, and intellectual disability/developmental delay. CNV analysis revealed a possible genetic etiology for 3 patients (13%). Additional WES in 1 of the 2 patients uncovered a novel heterozygous nonsense variant in Elongation factor Tu GTP-binding domain-containing 2 ( EFTUD2) causing mandibulofacial dysostosis with microcephaly (MFDM), which clinically overlaps with OAVS. Conclusion Detailed clinical evaluation for any patient with OAVS is recommended due to a high rate of accompanying systemic findings. We further expand the existing genetic heterogeneity of OAVS by identifying several CNVs and a phenotypically overlapping disorder, MFDM.

The role of genetic factors in microtia: A systematic review

“…10,15 The finding of biallelic pathogenic mutations in FGF3 on molecular genetic testing confirms the diagnosis of LAMM syndrome in the proband. 11,12,16,17 The TCOF1 gene, which encodes a suspected nucleolar phosphoprotein known as treacle, has been identified as the cause of TCS, 10,121 an autosomal dominant craniofacial development disorder, in up to 78% of patients. 18,110,122 Inhibition of mature RNA ribosomal (rRNA) production and gene transcription in neural folds prefusion during the early stage of embryogenesis may cause abnormal development due to treacle haploinsufficiency, caused by mutation in the TCOF1 gene, thus affecting proliferation and proper differentiation of these embryonic cells.…”

“…For example, FGF3 deletions in LAMM syndrome have been clinically identified as grade I microtia. 11,12,16,17 According to the MARX classification, 10 the HOXA2 gene was common in the form of microtia type II and was exclusive to isolated microtia, 1,13,14,[26][27][28][29]125,127,128 and no specific type of microtia has been linked to the deletion of TCOF1. 10,29 However this requires further studies to confirm these data.…”

“…Recently, other genetic studies using DNA chromosomal microarray analysis 12,13 , transcriptomic and proteomic profiles 14 and next-generation sequencing studies [15][16][17][18][19] have also been performed in patients with this entity, but few candidate genes have been identified so far. Therefore, more studies should be addressed in order to dilucidated the genetic etiology underlying of microtia which remains unknown in most patients.…”

“…Characteristic of the studies of syndromic microtia.11,12,[15][16][17][18][19][20][21][22][23][24][30][31][32][33][34][35][36][37][38][39][40][98][99][100][101][102][103][104]114,115 …”

Total Aplasia of Paranasal Sinus Associated With a Syndromic Condition

“…A TCS-like variant was considered because of the general syndromic face appearance, palpebral fissure shortening, wide protruding nasal base , high-narrow palate and clinodactyly whereas microtia, hearing loss and mandibular hypoplasia are not present. Furthermore, the diagnosis was not proven with a genetic test (Jurlaid et al, 2021; Gulenay et al, 2021; Lu et al, 2021).…”