Mutations and new polymorphic changes in the TCOF1 gene of patients with oculo–auriculo–vertebral spectrum and Treacher–Collins syndrome

Abstract

Oculo-auriculo-vertebral spectrum, the exact genetic predisposition of which has not yet been resolved, is characterized by varying degrees of the prevalently unilateral underdevelopment of craniofacial structures and spinal anomalies. Here, we analyzed four cases exhibiting multiple features of oculo-auriculo-vertebral spectrum and one case with Treacher-Collins syndrome. The cranium was analyzed using three-dimensional computed tomography, which reliably identifies craniofacial malformations. We detected one typical oculo-auriculo-vertebral spectrum patient who had a missense mutation in exon 9 of the TCOF1 gene complex and two silent mutations in exons 10 and 23, three partial oculo-auriculo-vertebral spectrum patients who had no detectable mutations in the TCOF1 gene complex, and one Treacher-Collins syndrome patient who had a nonsense mutation in exon 14. All five patients had eight previously reported polymorphic changes in the TCOF1 exons 10, 11, 12, 16, 21, 22, and 23, and four unreported polymorphisms in exons 9, 17, and 22 that were also detected in 51 Taiwanese control patients. These observations strongly suggest that the TCOF1 genetic changes observed in these five patients might be related to oculo-auriculo-vertebral spectrum symptoms.

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

“…Fischer et al (2006) found abnormal BAPX1 expression in a significant number of OAVS patients and suggested that epigenetic disregulation of BAPX1 might play a role in the etiology of OAVS. In addition, a few patients showing clinical overlap with OAVS had mutations in sal-like 1 (SALL1) (Kohlhase et al 1999;Keegan et al 2001;Kosaki et al 2007) or Treacher Collins-Franceschetti syndrome 1 (TCOF1) (Su et al 2007), the genes responsible for most cases of Townes-Brocks syndrome [OMIM 107480] and Treacher Collins syndrome [OMIM 154500], respectively, which are also associated with first and second branchial arch anomalies. Even though cytogenetic alterations have been associated with many cases of OAVS, most of the chromosomal aberrations are patient-specific, except that chromosome 5p (Choong et al 2003;Descartes 2006;Josifova et al 2004;Ala-Mello et al 2008) and 22q (Balci et al 2006;Xu et al 2008;Derbent et al 2003;Digilio et al 2009) have been implicated in a number of cases.…”

Facial asymmetry and clinical manifestations in patients with novel insertion of theTCOF1gene

“…Our finding of one of four HFM patients with a TCOF1 mutation (12) raised the possibility that TCOF1 mutations may play a role in a subset of patients with HFM. To test our hypothesis, we examined the genotype of the TCOF1 gene in 12 patients with HFM, and assessed the incidence of TCOF1 mutations with their characteristics.…”

“…Multiple genes contribute to the wide phenotypic spectra of the first and second branchial arch syndromes that include facial asymmetries (6, 7, 10–12, 24–26) and family members with the same mutation can exhibit distinct penetrance of the phenotype (2). Here, 6 of 12 patients diagnosed with HFM exhibited a novel frameshift mutation c. 4127 ins G in exon 24 in the TCOF1 gene.…”

“…Genetic mutations associated with HFM include to trisomy 10p14 (6), 22q11.2 microdeletion (7), 12p13.33→pter deletion (8), 10.7 cM on chromosome 14q32 (9), large 5p deletion (10), and gene mutations in SALL4 in a Goldenhar patient (11), and the TCOF1 gene (12). Mutations in the TCOF1 gene (chr5) were identified in 53–93% patients with the Treacher–Collins syndrome (TCS; OMIM: 154500) (12, 13). TCS also involves anomalies in the first and second branchial arches such as hypoplasia of the mandibular and zygomatic bones (14).…”

Hemifacial microsomia with pulmonary hypoplasia

“…The child in the present report did not have any limb or vertebral defects but had pulmonary hypoplasia. The other genetic syndromes to be considered in the differential diagnosis are: Nager acrofacial dysostosis, Treacher Collins–Franceschetti syndrome, Townes–Brocks syndrome, Beckwith–Weidemann syndrome (BWS) and Russell–Silver syndrome (RSS) 6 – 9. Nager acrofacial dysostosis combines the facial anomalies of mandibulofacial dysostosis (Treacher Collins–Franceschetti) with hypoplastic/aplastic or triphalangeal thumbs.…”