Two brothers with Burn-McKeown syndrome

Wieczorek, Dagmar; Teber, Özge Altug; Lohmann, Dietmar; Gillessen‐Kaesbach, Gabriele

doi:10.1097/01.mcd.0000072163.33788.c4

Cited by 11 publications

(16 citation statements)

References 4 publications

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“…We appreciate the remarks of Dr. Wieczorek and Dr. Gillessen‐Kaesbach regarding our recent description of four related individuals with choanal atresia, lower eyelid coloboma, cleft lip, external ear malformation, and hearing loss. We agree that there are similarities in the facial features of our “Patient 3” and “Cases 1 and 3” reported by Burn et al [1992] entitled “New dysmorphic syndrome with choanal atresia in siblings” and “Case 1” reported by Wieczorek et al [2003] entitled “Two brothers with Burn‐McKeown syndrome,” particularly with regard to eyelid colobomas, large ears, and prominent nose. In addition, we note there are anomalies common to both Burn‐McKeown syndrome (BMcKS) and the four Alaskan Native family members we reported with oculo‐oto‐facial dysplasia (OOFD) including: choanal atresia, lower eyelid defect, and normal intellect.…”

supporting

confidence: 84%

“…In addition, we note there are anomalies common to both Burn‐McKeown syndrome (BMcKS) and the four Alaskan Native family members we reported with oculo‐oto‐facial dysplasia (OOFD) including: choanal atresia, lower eyelid defect, and normal intellect. Observed differences between individuals with OOFD and BMcKS include: (1) hearing loss (100% OOFD; 50% BMcKS); (2) preauricular tags (100% OOFD; 12% BMcKS); and (3) primary palatal clefts (75% OOFD; 25% BMcKS) [Burn et al, 1992; Toriello and Higgins, 1999; Wieczorek et al, 2003]. These differences could reflect variable expressivity of allelic disorders due to a common gene or alternatively, genetic heterogeneity.…”

mentioning

confidence: 99%

“…These differences could reflect variable expressivity of allelic disorders due to a common gene or alternatively, genetic heterogeneity. It is important to note that all three BMcKS sibling‐pairs reported in the literature have been male [Burn et al, 1992; Wieczorek et al, 2003], and that the only known female BMcKS patient [Burn et al, 1992] did not have similar facial changes and was noted to have an abnormal karyotype [46, XX, r(18)(p14q23)]. This raises the possibility of X‐linked recessive inheritance in individuals with BMcKS.…”

mentioning

confidence: 99%

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Response to Wieczorek and Gillessen‐Kaesbach letter addressing “A Novel Oculo‐Oto‐Facial Dysplasia in a Native Alaskan Community With Autosomal Recessive Inheritance”

Hing

Parisi

2006

American J of Med Genetics Pt A

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supporting

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Response to Wieczorek and Gillessen‐Kaesbach letter addressing “A Novel Oculo‐Oto‐Facial Dysplasia in a Native Alaskan Community With Autosomal Recessive Inheritance”

Hing

Parisi

2006

American J of Med Genetics Pt A

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“…In one patient and his brother, we established the diagnosis Burn -McKeown syndrome. 26,27 Mutational analysis Genomic DNA was extracted from blood samples using Nucleon DNA extraction kits (Amersham Health, Ismaning, Germany). We used direct sequencing to identify mutations in the 27 exons and flanking splice sites of the TCOF1 gene.…”

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confidence: 99%

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

et al. 2004

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To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3 0 part of the open reading frame. Inter-and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.

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“…The primary phenotype associated with BMKS is choanal atresia, observed in all patients to date. Additional phenotypic features include conductive and sensorineural hearing loss and typical craniofacial dysmorphic features, including cleft lip and/or palate, short palpebral fissures, lower eyelid coloboma, a short philtrum, a prominent nose with high nasal bridge, and large protruding ears, while visceral malformations such as congenital heart defects are also sometimes observed [1][2][3][4][5][6]. Intellectual development is usually unimpaired, although at least one reported BMKS patient suffers severe intellectual disability and developmental delay [7].…”

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confidence: 99%

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

Wood

Rowlands

Thomas

et al. 2020

Preprint

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The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother-and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, splice site strengths and sequence motifs, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced KaryotypingKaryotyping of pluripotent iPSCs was conducted by the North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine. Apoptosis assaysCell apoptosis was assessed by annexin-V staining. For assessment of iPSCs, iPSC colonies were grown to approximately 60% confluency on VTN-treated 6-well tissue culture plates. For iNCCs, 120h differentiated iNCCs cultured on VTN-treated 6-well tissue culture plates were used. Cells were disrupted using trypsin-EDTA (Sigma) treatment and cells pelleted by centrifugation. Cells were washed once in PBS and then washed once in 1X Annexin-V Binding Buffer (ABB) (Invitrogen). The cells were resuspended at a density of 1 x 10 6 cells/ml in 1X ABB, and 7.5l APC-conjugated Annexin-V (Invitrogen) added to 100l cell suspension. The cells were incubated for 20min at room temperature in the dark, washed in 1X ABB and resuspended in 200l 1X ABB. 0.25g/ml DAPI (Invitrogen) was added and the resulting samples immediately analysed by flow cytometry. Subpopulations were ascertained in a BD LSRFortessa flow cytometer (gated using an unstained control) as f...

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Two brothers with Burn-McKeown syndrome

Cited by 11 publications

References 4 publications

Response to Wieczorek and Gillessen‐Kaesbach letter addressing “A Novel Oculo‐Oto‐Facial Dysplasia in a Native Alaskan Community With Autosomal Recessive Inheritance”

Response to Wieczorek and Gillessen‐Kaesbach letter addressing “A Novel Oculo‐Oto‐Facial Dysplasia in a Native Alaskan Community With Autosomal Recessive Inheritance”

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

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