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PubMed1988

Discordance of signs in monozygotic twins concordant for the Goldenhar anomaly.

Concordance for Goldenhar anomaly has been described in monozygotic (MZ) twins on 2 occasions but never in dizygotic (DZ) twins. In both cases the twins were similarly, although not identically, affected. We report on a pair of probably monozygotic twins (8% probability of DZ) who presented with extremely diverse manifestations of this anomaly complex. One of them required a tracheostomy because of obstructive apnea due to severe micrognathia and subsequently died. This twin had a midline lower lip cleft which has not previously been described in the Goldenhar anomaly.

Diseases in Twins↗
PubMed1988

Multiple congenital anomaly/mental retardation (MCA/MR) syndrome with Goldenhar complex due to a terminal del(22q).

We present a case of terminal del(22q) with Goldenhar complex including hemifacial microsomia, bilateral epibulbar dermoids, preauricular tags with sensorineural hearing loss, vertebral anomalies, and CNS and renal malformations. The case illustrates causal heterogeneity of the Goldenhar complex and a previously unreported associated chromosome deletion.

Abnormalities, Multiple↗
PubMed1988

Evaluating the uncertainty of risk prediction in genetic counseling: a Bayesian approach.

A general method to obtain the exact point estimate and the measure of uncertainty of recurrence risks for genetic counseling is present. This method, which follows Bayesian estimation theory, can be applied without restrictions of sample size, class of risk function, or parameter dimension. As an illustration, the recurrence risks for isolated cases in two autosomal dominant disorders with incomplete penetrance (mandibulofacial and fontonasal dyostoses) are estimated.

Bayes Theorem↗
PubMed1988

Oculoauriculovertebral anomaly: variability and causal heterogeneity.

The oculoauriculovertebral anomaly is a complex developmental field defect. There is lack of agreement on the minimal diagnostic criteria and the phenotypic spectrum. Causal heterogeneity has been described. This report reviews aspects of phenotypic variability and causal heterogeneity and discusses current understanding of the defect.

Female↗
PubMed1989

Acrofacial dysostoses.

A female baby was born with phocomelia, bilateral cleft lip and palate, marked micrognathia, malar hypoplasia, absence of lower eyelids, and absence of external ears. Radiological examination showed hypoplastic pectoral and pelvic girdles, short humeri and femora, with absence of forearms and legs, and oligodactyly of upper limbs. Her mother has triphalangism of the left thumb and a hypoplastic right thumb with stiff metacarpophalangeal joint. She also has downward-slanting palpebral fissures, malar hypoplasia, and deepset eyes. This observation offers an opportunity to revisit the acrofacial dysostoses syndromes, including Nager-Reynier syndrome, Genée-Wiedeman syndrome, and lethal forms.

Abnormalities, Multiple↗
PubMed1993

Co-occurrence of schizophrenia and Treacher Collins syndrome.

This is the first report of an individual with several congenital abnormalities, including those suggestive of Treacher Collins syndrome, and an atypical schizophrenic illness. Cytogenetic studies have failed to detect any recognizable chromosomal abnormality.

Humans↗
PubMed2003

Novel mutation in the 5' splice site of exon 4 of the TCOF1 gene in the patient with Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is caused by mutations in the TCOF1 gene. This gene encodes a serine/alanine-rich protein called treacle. The structure of the entire TCOF1 gene was investigated in a patient with TCS. We detected a novel deletion (376delAAGGTGAGTGGGACTGCC) spanning 3 bp of exon 4 and 15 bp of the adjacent intronic sequence. This mutation causes premature termination of translation, resulting in a truncated protein devoid of nucleolar localization signal, and potential phosphorylation sites. Real-time PCR analysis showed different melting temperatures of the amplified fragment containing normal allele and that harboring the 18 bp deletion, thus providing a rapid screening assay for this and other deletions of the TCOF1 gene.

Base Sequence↗
PubMed2004

Identification of mutations in TCOF1: use of molecular analysis in the pre- and postnatal diagnosis of Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of facial development, which results from mutations in TCOF1. TCS comprises conductive hearing loss, hypoplasia of the mandible and maxilla, downward sloping palpebral fissures and cleft palate. Although, there is usually a reasonable degree of bilateral symmetry, a high degree of both inter- and intrafamilial variability is characteristic of TCS. The wide variation in the clinical presentation of different patients, together with the fact that more than 60% of cases arise de novo, can complicate the diagnosis of mild cases and genetic counselling. In the current study, we describe how molecular techniques have been used to facilitate pre- and postnatal disease diagnoses in 13 TCS families.

Female↗
PubMed2004

Treacher Collins syndrome with craniosynostosis, choanal atresia, and esophageal regurgitation caused by a novel nonsense mutation in TCOF1.

Treacher Collins syndrome (TCS) is caused by mutations in TCOF1 of the nonsense, small deletion, and small insertion types, which most likely result in haploinsufficiency. We report a novel de novo nonsense mutation 2731C --> T, resulting in Arg911Stop, which truncates the protein. Our patient had the classic findings of TCS, but with documented craniosynostosis, choanal atresia, and esophageal regurgitation.

Arginine↗
PubMed2005

Mutational analysis of the TCOF1 gene in 11 Japanese patients with Treacher Collins Syndrome and mechanism of mutagenesis.

Treacher Collins Syndrome (TCS) (OMIM 154500) is a congenital, craniofacial disorder inherited as an autosomal dominant trait. The responsible gene for TCS, TCOF1, was mapped to 5q32-33.1 and identified in 1996. Since then, TCOF1 mutations in patients with TCS have been reported from Europe, North and South America, however, no TCS cases from an Asian country have been molecularly characterized. Here we report mutational analysis for 11 Japanese patients with TCS for the first time, and have identified TCOF1 mutations in 9 of them. The mutations detected were various, but most likely all the mutations are predicted to result in a truncated gene product, known as treacle. One mutation frequently reported was included in our cases, but no missense mutations were detected. These findings are similar to those for the previous studies for TCS in other races. We have speculated about the molecular mechanisms of the mutations in most cases. Collectively, we have defined some of the characteristic molecular features commonly observed in TCS patients, irrespective of racial difference.

Base Sequence↗
PubMed1987

Anthropometric evaluation of dysmorphology in craniofacial anomalies: Treacher Collins syndrome.

Advances in surgical techniques for correction of craniofacial anomalies have necessitated the development of objective pre- and postoperative quantitative assessments. Standard anthropometric techniques, supplemented by additional methods oriented to specific clinical problems, have proved useful in defining surface dysmorphology in craniofacial patients. A series of 77 surface measurements of the head and face and 41 proportions were determined in 20 preoperative patients with Treacher Collins syndrome, a rare congenital defect of the first and second branchial arches. To permit comparison with age- and sex-specific data for healthy North American children, the patient data were converted to standard (Z) scores. To test the hypothesis Z = 0, Student's t-test was performed on all variables. The anthropometric findings verified many of the clinical findings in this syndrome. In addition, a number of previously unreported defects were found. The cranium was low and short with a low, narrow forehead and a narrow cranial base. The face was narrow and shallow, the mandible long and narrow, and the lower face receding. The eye fissures were short with an antimongoloid inclination, but the orbits were hyperteloric. The nasal root was high and wide, the nasofrontal angle open, and the bridge inclination low. The labial fissure was narrow, and the ears were microtic. Except in the nasal root the defects were hypoplastic. Most of these defects were either horizontal or anteroposterior. Recognition of the defective areas and their contribution to disproportions of the head and face is important in the development of surgical strategies.

Adolescent↗
PubMed2004

The neural crest: basic biology and clinical relationships in the craniofacial and enteric nervous systems.

The highly migratory, mesenchymal neural crest cell population was discovered over 100 years ago. Proposals of these cells' origin within the neuroepithelium, and of the tissues they gave rise to, initiated decades-long heated debates, since these proposals challenged the powerful germ-layer theory. Having survived this storm, the neural crest is now regarded as a pluripotent stem cell population that makes vital contributions to an astounding array of both neural and non-neural organ systems. The earliest model systems for studying the neural crest were amphibian, and these pioneering contributions have been ably refined and extended by studies in the chick, mouse, and more recently the fish to provide detailed understanding of the cellular and molecular mechanisms regulating and regulated by the neural crest. The key questions regarding control of craniofacial morphogenesis and innervation of the gut illustrate the wide range of developmental contexts in which the neural crest plays an important role. These questions also focus attention on common issues such as the role of growth factor signaling in neural crest cell development and highlight the central role of the neural crest in human congenital disease.

Animals↗
PubMed2001

Msx2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells.

During early mouse embryogenesis, cranial neural crest cells (CNCC) emigrate from the posterior midbrain and rhombomeres 1 and 2 of the anterior hindbrain into the first branchial arch-derived maxillary and mandibular processes and there provide cell lineages for several phenotypes, including cartilage, bone, and tooth. Here, we report that Sox9 and Msx2 were coexpressed in a subpopulation of CNCC during their migration. Because Sox9 is a transactivator of chondrogenesis, and Msx genes can act as transcriptional repressors, we hypothesized that Sox9 expression indicates the determination of CNCC-derived chondrogenic cell lineage and that Msx2 represses chondrogenic differentiation until CNCC migration is completed within the mandibular processes. To test whether Msx2 represses chondrogenesis, we designed experiments to inhibit Msx2 function in migratory CNCC in primary cultures through the expression of loss-of-function Msx2 mutants. We showed that infection of migratory CNCC with adenovirus Msx2 mutants accelerated the rate and extent of chondrogenesis, as indicated by the expression level of type II collagen and aggrecan, and the amount of alcian blue staining. Adenovirus infections did not apparently interfere with CNCC proliferation or migration. These findings suggest that an important early event in craniofacial morphogenesis is a transient expression of both Sox9 and Msx2 during emigration into the forming mandibular processes followed by restricted expression of Sox9 within CNCC- derived chondroprogenitor cells. We conclude that Msx2 serves as a repressor of chondrogenic differentiation during CNCC migration.

Adenoviridae↗
PubMed2004

Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle.

Treacher Collins syndrome (TCS) is a craniofacial disorder that results from mutations in TCOF1, which encodes the nucleolar protein Treacle. The severity of the clinical features exhibits wide variation and includes hypoplasia of the mandible and maxilla, abnormalities of the external ears and middle ear ossicles, and cleft palate. To determine the in vivo function of Treacle, we previously generated Tcof1 heterozygous mice on a mixed C57BL/6 and 129 background. These mice exhibited a lethal phenotype, which included abnormal development of the maxilla, absence of the eyes and nasal passages, and neural tube defects. Here, we show that placing the mutation onto different genetic backgrounds has a major effect on the penetrance and severity of the craniofacial and other defects. The offspring exhibit markedly variable strain-dependent phenotypes that range from extremely severe and lethal in a mixed CBA/Ca and 129 background, to apparently normal and viable in a mixed BALB/c and 129 background. In the former case, in addition to a profoundly severe craniofacial phenotype, CBA-derived heterozygous mice also exhibited delayed ossification of the long bones, rib fusions, and digit anomalies. The results of our studies indicate that factors in the different genetic backgrounds contribute extensively to the Tcof1 phenotype.

Animals↗
PubMed2005

TCOF1 mutation database: novel mutation in the alternatively spliced exon 6A and update in mutation nomenclature.

Recently, a novel exon was described in TCOF1 that, although alternatively spliced, is included in the major protein isoform. In addition, most published mutations in this gene do not conform to current mutation nomenclature guidelines. Given these observations, we developed an online database of TCOF1 mutations in which all the reported mutations are renamed according to standard recommendations and in reference to the genomic and novel cDNA reference sequences (www.genoma.ib.usp.br/TCOF1_database). We also report in this work: 1) results of the first screening for large deletions in TCOF1 by Southern blot in patients without mutation detected by direct sequencing; 2) the identification of the first pathogenic mutation in the newly described exon 6A; and 3) statistical analysis of pathogenic mutations and polymorphism distribution throughout the gene.

Alternative Splicing↗
PubMed2026

Molecular Characterisation of Treacher Collins Syndrome in a South African Cohort: Novel Disease-Causing Variants in TCOF1 and POLR1D.

BACKGROUND: Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterised by variable expressivity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, or POLR1B genes. Common clinical features include hypoplasia of the zygomatic complex and mandible, downward-slanting palpebral fissures, lower eyelid anomalies, microtia, and hearing loss. Owing to its phenotypic overlap with other craniofacial syndromes, molecular testing is essential for establishing an accurate diagnosis and guiding effective clinical management. METHODS: Ten South African patients with a suspected clinical diagnosis of TCS underwent targeted next-generation sequencing (NGS) using a custom gene panel including TCOF1, POLR1C, and POLR1D genes. Variants were classified according to ACMG/AMP guidelines, with validation by Sanger sequencing where necessary. RESULTS: Disease-causing variants were identified in six of the ten patients (60%). These included five heterozygous variants in TCOF1 and one homozygous variant in POLR1D. Notably, five of the six variants were identified for the first time in this study. Additionally, a recurrent TCOF1 deletion was identified for the first time in an African family. CONCLUSION: This study expands the mutational spectrum of TCS in general and provides African data in particular. Findings support the use of panel-based NGS for diagnosis in resource-limited settings and highlight the need for population-specific variant data to improve diagnostic accuracy, guide clinical care, and support genetic counselling for affected individuals and their families.

Humans↗
PubMed2026

Novel TCOF1 Frameshift Variant and Phenotypic Heterogeneity in a Chinese Family With Treacher Collins Syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) is a congenital craniofacial disorder characterized by malar and mandibular hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. Pathogenic variants in TCOF1 account for most cases, with POLR1D, POLR1C, and POLR1B also implicated. METHODS: Whole-exome sequencing was performed in a two-generation Chinese family with TCS, followed by Sanger sequencing validation. Clinical features were systematically evaluated, and bioinformatic analyses combined with structural modeling were employed to assess the potential pathogenicity of the identified variant. RESULTS: In this study, a novel heterozygous frameshift variant in TCOF1 (NM_001371623.1:c.1601_1602delCC, p.Pro534Leufs*15) was identified in the proband and his affected father. The proband presented classic TCS features including craniofacial skeletal hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. He also carried a right-sided preauricular fistula, a nonclassical feature of TCS. The same variant was detected in his affected father with a substantially milder phenotype, indicating marked intrafamilial phenotypic variability. Bioinformatic analysis and structural modeling predicted that this variant produces a severely truncated Treacle protein lacking key functional domains, which is predicted to disrupt nucleolar localization and ribosome biogenesis. CONCLUSION: Our findings expand the variant spectrum of TCOF1, highlight phenotypic heterogeneity in TCS, and reinforce the critical role of molecular diagnosis in distinguishing TCS from phenotypically overlapping craniofacial syndromes.

Humans↗