Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.
Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.
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扩大 Burn-McKeown 综合征中 TXNL4A 变异的基因型谱。
DOI：
10.1111/cge.14082
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发表时间：
2022
影响因子：
3.5
通讯作者：
Wood KA
中科院分区：
文献类型：
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作者：
Wood KA
发育障碍Burn-McKeown综合征（BMKS）的特征是后鼻孔闭锁和特定的颅面特征。BMKS是由前信使RNA剪接因子TXNL 4A中的双等位基因变体引起的。大多数患者在启动子区存在34个碱基对（bp）缺失（1型Δ34）的反式功能缺失变体。在这里，我们确定了两名BMKS患者。一个个体具有与1型Δ34启动子缺失组合的aTXNL4Ac.93_94delCC，p.His32Argfs *21变体。另一个具有内含子TXNL 4Asplice位点变体（c.258 - 3C>G）和1型Δ34启动子缺失。我们发现c.258 - 3C>G变异体和先前报道的c.258 - 2A>G变异体在小基因剪接试验中导致TXNL 4A的最后一个外显子跳跃。此外，我们还鉴定了TXNL 4A启动子56 bp内受1型和2型Δ34影响的转录因子结合位点，并使用双荧光素酶测定法鉴定了该启动子区域内TXNL 4A表达所必需的22 bp重复基序。我们建议，额外的变异影响关键转录因子结合核苷酸内的22 bp重复基序可能与BMKS病因。最后，我们的数据强调需要分析个体中的非编码序列，其中在与临床表现一致的常染色体隐性遗传病中鉴定出单个可能的致病性编码变体。
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 factorTXNL4A. Most patients have a loss‐of‐function variant intranswith a 34‐base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has aTXNL4Ac.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronicTXNL4Asplice site variant (c.258‐3C>G) and a type 1 Δ34 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 ofTXNL4Ain a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of theTXNL4Apromoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential forTXNL4Aexpression 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.