Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome

CLINICAL GENETICS(2022)

引用 2|浏览30
暂无评分
摘要
The developmental disorder Burn-McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre-messenger RNA splicing factor TXNL4A. Most patients have a loss-of-function variant in trans with a 34-base pair (bp) deletion (type 1 Delta 34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Delta 34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258-3C>G) and a type 1 Delta 34 promoter deletion. We show the c.258-3C>G variant and a previously reported c.258-2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Delta 34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation.
更多
查看译文
关键词
Burn-McKeown syndrome, choanal atresia, craniofacial abnormalities, DIM1, non-coding variant, promoter, RNA splicing, spliceosome, TXNL4A
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要