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. © 1993 Wiley-Liss, Inc.     

Two extraordinarily severe cases of Treacher Collins syndrome

Here, we report two extraordinarily severe cases of Teacher Collins syndrome. Initially, amniotic bands and plical fold disruption were considered, but downslanting eyes made us consider severe Treacher Collins syndrome. A TCOF1 mutation in exon 24 was identified in Patient 1 (c.4355_4356ins14, resulting in p.1456Thrfs*18). Patient 2, who expired on day 4, is so similar to Patient 1 that severe Treacher Collins syndrome may be inferred in this instance. Neither the TCOF1 mutation nor the well‐known variability in the expression in affected families with Treacher Collins syndrome (～40% of reported cases) can explain the severity of these cases; otherwise, we would be aware of such cases within families from time to time. We are unaware of any recent sporadic cases (～60% of reported cases) exactly like ours either with a single exception in the case reported by Writzl et al. [ 2008 ] with a TCOF1 mutation. The case described by Otto in 1841 is spectacular. We propose several hypotheses to be considered in explaining this developmental amplification, including some promoter effect on the gene, some position effect on the gene, a polymorphism elsewhere in the gene, a point mutation elsewhere in the gene, a polymorphism in another gene, or a point mutation in another gene, such as POLR1C (which maps to 6p21.1) or POLR1D (which maps to13q12.2). We also review the etiology and pathogenesis of Treacher Collins syndrome, and discuss several other severe cases from the past. © 2013 Wiley Periodicals, Inc.     

Exploring the genetic origins of Treacher Collins syndrome

Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome Dauwerse et al. (2011) Nature Genetics 43:20–22     

Prenatal diagnosis in Treacher Collins syndrome using combined linkage analysis and ultrasound imaging.

Treacher Collins syndrome is an autosomal dominant disorder of facial development, the features of which include conductive hearing loss and cleft palate. In the current investigation, linkage analysis has been used to make first trimester diagnostic predictions in a pregnancy at high risk of producing an affected child. The results of this analysis predicted that the child would be affected. As predictions of the severity of the disease were not possible, the pregnancy was also assessed by ultrasound imaging. This confirmed the affected diagnosis and predicted that the child would be severely affected.     

Reduced transcription of TCOF1 in adult cells of Treacher Collins syndrome patients

Background  

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder caused by frameshift deletions or duplications in the TCOF1 gene. These mutations cause premature termination codons, which are predicted to lead to mRNA degradation by nonsense mediated mRNA decay (NMD). Haploinsufficiency of the gene product (treacle) during embryonic development is the proposed molecular mechanism underlying TCS. However, it is still unknown if TCOF1 expression levels are decreased in post-embryonic human cells.     

Parental origin of mutations in sporadic cases of Treacher Collins syndrome

In some autosomal dominant conditions, there is a correlation between new mutations and paternal age, with new mutations arising almost exclusively in the male germ line. To test this hypothesis in Treacher Collins syndrome, we analyzed 22 sporadic cases, determining the parental origin of the pathogenic mutation in 10 informative families. Mutations were found to be of both paternal and maternal origin, without a detectable parental age effect, confirming that a paternal age effect is not universal to all autosomal dominant disorders. A discussion on the parental origin of mutations and paternal age effect in other diseases is included.     

Salivary gland pathology as a new finding in Treacher Collins syndrome

In our clinical experience, individuals with Treacher Collins syndrome (TCS) present with more complaints of oral dryness and higher caries activity than seen in the general population. A literature review identified no reports of salivary gland pathology and glandular dysfunction associated with TCS. Twenty-one Norwegian individuals with TCS underwent ultrasound examinations and salivary secretion tests of the submandibular and parotid glands. Intraglandular architecture patterns were analyzed and subsequently classified as either normal, dysplastic, or aplastic. The results were compared with salivary secretion rates and subjective reports of oral dryness. Ultrasound examination revealed pathological appearance of the salivary glands in approximately half (48%) of the individuals, with dysplasia identified in six (29%) participants and aplasia in four (19%). Almost all participants had co-existing low salivary secretion rates. A few individuals had low salivary secretion rates despite normal appearance of the salivary gland tissue on ultrasound examination. Subjective experience of oral dryness did not correlate significantly with low salivary secretion rates. We conclude that mild to severe salivary gland pathology and dysfunction can be associated with TCS. Further investigation is needed to clarify this association.     

Exclusion of Treacher Collins Franceschetti syndrome in a subject with tetralogy of Fallot and cryptorchidism

Genotyping with flanking DNA markers was used to ascertain Treacher Collins Franceschetti syndrome (TCOF1) in a subject affected by tetralogy of Fallot and cryptorchidism. The proband's family consisted of a father and sister who were affected by the disease, and a healthy mother. Since cardiac malformation and cryptorchidism have been associated with the TCOF1 syndrome, the proband was suspected to be a carrier of the mutated gene. Microsatellite markers D5S527, SPARC and D5S519, which previously mapped the TCOF1 gene within a 2.1-cM interval on chromosome 5 (5q32–33.1), were used to follow the transmission of the TCOf 1 mutated locus. Flanking markers D5S519 and D5S527 were informative and enabled us to exclude inheritance of a TCOF1 mutation to the proband, while showing that cardiac malformation and cryptorchidism were unrelated in mis patient.     

Molecular and phenotypic variation in patients with severe Hunter syndrome

Severe Hunter syndrome is a fatal X-linked lysosomal storage disorder caused by iduronate-2-sulphatase (IDS) deficiency. Patients with complete deletion of the IDS locus often have atypical phenotypes including ptosis, obstructive sleep apnoea, and the occurrence of seizures. We have used genomic DNA sequencing to identify several new genes in the IDS region. DNA deletion patients with atypical symptoms have been analysed to determine whether these atypical symptoms could be due to involvement of these other loci. The occurrence of seizures in two individuals correlated with a deletion extending proximal of IDS, up to and including part of the FMR2 locus. Other (non-seizure) symptoms were associated with distal deletions. In addition, a group of patients with no variant symptoms, and a characteristic rearrangement involving a recombination between the IDS gene and an adjacent IDS pseudogene (IDS psi), showed normal expression of loci distal to IDS. Together, these results identify FMR2 as a candidate gene for seizures, when mutated along with IDS.      

Mosaicism of a TCOF1 mutation in an individual clinically unaffected with Treacher Collins syndrome

Treacher Collins syndrome (TCS) or mandibulofacial dysostosis is an autosomal dominant disorder of craniofacial development with 60% of its cases arising de novo. Other modes of inheritance such as autosomal recessive, gonadal mosaicism, and chromosomal rearrangement have also been proposed. This syndrome can result from TCOF1 gene mutations. In this study we identified a TCOF1 1408delAG heterozygous mutation in a patient with the clinical diagnosis of TCS. This same mutation was found in the clinically unaffected mother's leukocytes, hair root bulbs, buccal mucosa, urine, and stool. The mother has a clinically unaffected child and the maternal grandparents do not have the mutation. Because the mother has the mutation in cells derived from all three germ layers, we suspected the mutation was nonpenetrant. However, we could not detect the mutation in her skin fibroblasts, suggesting she is mosaic secondary to cell type specific selection.     

Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

PurposeTreacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C.MethodsWe report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype–genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene.ResultsWe identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature.ConclusionEven though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype–genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.     

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.     

POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4

PurposeTreacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2–1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.MethodsWe performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.ResultsWe identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives.ConclusionPathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.     

Treacher Collins syndrome: Phenotypic variability in a family including an infant with arhinia and uveal colobomas

We report extreme expression of Treacher Collins syndrome in an infant with arhinia, anotia, absent zygomatic bones, hypoplastic mandibular rami, and bilateral coloboma of iris, choroid plexus, and optic nerves. The Treacher Collins phenotype was mildly expressed in the mother and moderately in the sister. The father had no signs and was not ruled out as the father by DNA fingerprinting, thus making homozygosity by descent in the severely affected son very unlikely. © 1995 Wiley-Liss, Inc.     

Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS gene ( TCOF1 ), which is localized to chromosome 5q32-q33.1, recently has been identified by positional cloning. Analysis of TCOF1 revealed that the majority of TCS mutations result in the creation of a premature termination codon. The function of the predicted protein, treacle, is unknown, although indirect evidence from database analyses suggests that it may function as a shuttling nucleolar phosphoprotein. In the current study, we provide the first direct evidence that treacle is a nucleolar protein. An antibody generated against treacle shows that it localizes to the nucleolus. Fusion proteins tagged to a green fluorescent protein reporter were shown to localize to different compartments of the cell when putative nuclear localization signals were deleted. Parallel experiments using conserved regions of the murine homologue of TCOF1 confirmed these results. Site-directed mutagenesis has been used to recreate mutations observed in individuals with TCS. The resulting truncated proteins are mislocalized within the cell, which further supports the hypothesis that an integral part of treacle's function involves shuttling between the nucleolus and the cytoplasm. TCS is, therefore, the first Mendelian disorder resulting from mutations which lead to aberrant expression of a nucleolar protein.      

High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes

Twenty-eight families with a clinical diagnosis of Treacher Collins syndrome were screened for mutations in the 25 coding exons of TCOF1 and their adjacent splice junctions through SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients, yielding the highest detection rate reported so far for this disease (93%) and bringing the number of known disease-causing mutations from 35 to 51. This is the first report to describe clustering of pathogenic mutations. Thirteen novel polymorphic alterations were characterized, confirming previous reports that TCOF1 has an unusually high rate of single-nucleotide polymorphisms (SNPs) within its coding region. We suggest a possible different mechanism leading to TCS or genetic heterogeneity for this condition, as we identified two families with no apparent pathogenic mutation in the gene. Furthermore, our data confirm the absence of genotype-phenotype correlation and reinforce that the apparent anticipation often observed in TCS families is due to ascertainment bias.