OTX2duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

Abstract

BackgroundOculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.MethodsWe described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects ofOTX2overexpression in a zebrafish model.ResultsWe defined a 272 kb minimal common region that only overlaps with theOTX2gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression ofOTX2in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.ConclusionsOur results indicate that properOTX2dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated thatOTX2genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.

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.…”

“…2 FGF3 mutations are commonly found in LAMM syndrome. 11,12 The FGF3 protein regulates a cascade of chemical processes inside cells by binding to its receptor, thereby signaling cells to undergo particular changes, such as proliferating or maturing to perform specialized activities. 109 TCOF1 mutations can cause TCS in up to 78% of 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 …”