Dataset Information

Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.

ABSTRACT: Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34?bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1?) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1? promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2?)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia.

SUBMITTER: Goos JAC

PROVIDER: S-EPMC5602009 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.

Goos Jacqueline A C JAC Swagemakers Sigrid M A SMA Twigg Stephen R F SRF van Dooren Marieke F MF Hoogeboom A Jeannette M AJM Beetz Christian C Günther Sven S Magielsen Frank J FJ Ockeloen Charlotte W CW A Ramos-Arroyo Maria M Pfundt Rolph R Yntema Helger G HG van der Spek Peter J PJ Stanier Philip P Wieczorek Dagmar D Wilkie Andrew O M AOM van den Ouweland Ans M W AMW Mathijssen Irene M J IMJ Hurst Jane A JA

European journal of human genetics : EJHG 20170726 10

Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site v ...[more]

PMID: 28905882

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Project description: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 physical 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 TXNL4A expression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.

Dataset Information

Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.

Publications

Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia.

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