PDF(Pubmed)
Abstract：
BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease.
METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.
RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts.
CONCLUSIONS: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.
METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.
RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts.
CONCLUSIONS: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.
摘要：
背景：神经丛蛋白是信号蛋白的信号蛋白家族的大型跨膜受体。Semaphorin-plexin信号传导控制在发育以及成人生命阶段至关重要的细胞相互作用。已经在人类中鉴定出9个神经丛蛋白基因，但是尽管神经丛在发育中很重要，迄今为止,只有双等位基因PLXND1和PLXNA1变异体与孟德尔遗传病相关.
方法：来自6个家庭的8个人表现为隐性遗传可变的临床状况，具有釉质发育不全（AI）和感音神经性听力损失（SNHL）的核心特征，具有可变的智力残疾。通过外显子组或基因组测序研究前带。排除了常见变体和不太可能影响功能的变体。与常染色体隐性遗传一致的变异体被优先考虑。通过Sanger测序进行变体分离分析。在C57Bl6小鼠中进行RNA表达分析。
结果：丛蛋白B2（PLXNB2）的罕见双等位基因致病变异，一种大的跨膜信号素受体蛋白，在所有六个家庭中都被发现与疾病隔离。识别的变体包括错义，胡说，剪接变化和多外显子缺失。在分化成釉细胞中检测到Plxnb2表达。
结论：我们确定PLXNB2中罕见的双等位基因致病变异是新的常染色体隐性遗传的原因，以AI和SNHL为核心特征的表型多样性综合征。智力残疾,眼部疾病,耳朵发育异常和淋巴水肿也出现在多个病例中。可变的综合征人类表型与Plxnb2敲除小鼠中看到的重叠，and,加上人类PLXNB2变体的稀有性，可以解释为什么PLXNB2中的致病性变异以前没有报道。
方法：来自6个家庭的8个人表现为隐性遗传可变的临床状况，具有釉质发育不全（AI）和感音神经性听力损失（SNHL）的核心特征，具有可变的智力残疾。通过外显子组或基因组测序研究前带。排除了常见变体和不太可能影响功能的变体。与常染色体隐性遗传一致的变异体被优先考虑。通过Sanger测序进行变体分离分析。在C57Bl6小鼠中进行RNA表达分析。
结果：丛蛋白B2（PLXNB2）的罕见双等位基因致病变异，一种大的跨膜信号素受体蛋白，在所有六个家庭中都被发现与疾病隔离。识别的变体包括错义，胡说，剪接变化和多外显子缺失。在分化成釉细胞中检测到Plxnb2表达。
结论：我们确定PLXNB2中罕见的双等位基因致病变异是新的常染色体隐性遗传的原因，以AI和SNHL为核心特征的表型多样性综合征。智力残疾,眼部疾病,耳朵发育异常和淋巴水肿也出现在多个病例中。可变的综合征人类表型与Plxnb2敲除小鼠中看到的重叠，and,加上人类PLXNB2变体的稀有性，可以解释为什么PLXNB2中的致病性变异以前没有报道。
