Microarray-Based Comparative Genomic Hybridization, Multiplex Ligation-Dependent Probe Amplification, and High-Resolution Karyotype for Differential Diagnosis Oculoauriculovertebral Spectrum: A Systematic Review

Abstract

Oculoauriculovertebral spectrum (OAVS) is a rare class of heterogenous congenital craniofacial malformation conditions of unknown etiology. Although classic OAVS has been described as hemifacial microsomia with facial asymmetry and microtia, there is no consensus regarding clinical criteria for diagnosis or genetic cause. This systematic review aims to assess the applicability of high-resolution (HR) karyotype, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA), and microarray-based comparative genomic hybridization (array-CGH) for differential diagnosis of OAVS. A search was performed in PubMed and Web of Science using all entry terms to the following descriptors: Goldenhar's syndrome, cytogenetic analysis, hybridization in situ, fluorescent, comparative genomic hybridization, multiplex polymerase chain reaction, whole genome sequencing, and karyotype analysis methods. After screening, 25 articles met eligibility. Of the included studies, 59 individuals had a genetic alteration identified. Array-CGH, MLPA, and HR karyotype appear to be viable approaches for molecular diagnosis in OAVS. Heterogeneity is a hallmark of OAVS. Establishing an enhanced framework for diagnosis would inform clinical decision making, and better resource utilization could improve health care facility efficiency and economy.

The role of genetic factors in microtia: A systematic review

“…HOXA2 was discovered to be highly expressed in the second brachial arches (BA2), to express critical developmental transcription factors BA2, to play an important role in the development of the external and middle ear during embryonic development, and to be associated with autosomal recessive bilateral microtia as a member of the HOX gene family. 10,13,25 In humans, abnormal or lost HOXA2 function, as well as early and late HOXA2 inactivation, results in auditory system malformations, primarily in the external and middle ear, such as a duplicated or absent auricle 10,25 Consequently, HOXA2 has been proposed as a key transcriptional regulator of auricle morphogenesis. 125 Individuals with a homozygous HOXA2 mutation have far more severe clinical symptoms than those with a heterozygous mutation.…”

“…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.…”

“…110 HOXA2 encodes key developmental transcription factors of the second branchial arch, which contributes significantly to the development of the external and middle ear in embryonic development, and it was previously linked to autosomal recessive bilateral microtia. 10,13 Eligibility criteria We performed an extensive and systematic search of all published studies related to genetic factors implicated in the development or outcome of microtia. Rather than focusing on a single disease, we aimed to provide systematic evidence on all types of microtia, including isolated microtia and syndromic microtia.…”

“…Paragraph "FGF3 mutations are commonly found in LAMM syndrome. 13,14 (…) TCOF1 mutations can cause TCS in up to 78% of patients. (…) HOXA2….…”