Abstract：
OBJECTIVE: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function (LoF) LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs).
METHODS: 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions.
RESULTS: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling.
CONCLUSIONS: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.
METHODS: 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions.
RESULTS: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling.
CONCLUSIONS: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.
摘要：
目的：致病性LZTR1变异体可导致神经鞘瘤病和显性/隐性Noonan综合征（NS）。我们的目标是在杂合功能丧失（LoF）LZTR1等位基因与分离的多个咖啡壶斑（CaLMs）之间建立关联。
方法：849名具有多个CaLM的无关参与者，缺乏致病性/可能致病性NF1和SPRED1变体，进行了RASopathy基因组测序。收集125个具有杂合LZTR1变体的个体的数据以表征其临床特征和相关的分子谱。对错义变体和小框内缺失的代表性小组进行体外功能评估。
结果：分析显示，6.0%（51/849）的参与者中存在杂合的LZTR1变异，超过一般人群患病率。与LZTR1相关的CaLM数量不同，显示尖锐或不规则的边界，通常是孤立的，但偶尔与放射病中重复出现的特征有关。在两个家庭中，CaLM和神经鞘瘤共同发生。分子光谱主要由截短变体组成，表示LoF。这些变体与神经鞘瘤病和隐性NS中发生的变体基本上重叠。功能表征显示加速的蛋白质降解或错误定位，和未能下调MAPK信号。
结论：我们的发现扩大了与LZTR1变异相关的表型变异，which,除了赋予神经鞘瘤病易感性和引起显性和隐性NS，发生在具有孤立的多个CaLMs的个体中。
方法：849名具有多个CaLM的无关参与者，缺乏致病性/可能致病性NF1和SPRED1变体，进行了RASopathy基因组测序。收集125个具有杂合LZTR1变体的个体的数据以表征其临床特征和相关的分子谱。对错义变体和小框内缺失的代表性小组进行体外功能评估。
结果：分析显示，6.0%（51/849）的参与者中存在杂合的LZTR1变异，超过一般人群患病率。与LZTR1相关的CaLM数量不同，显示尖锐或不规则的边界，通常是孤立的，但偶尔与放射病中重复出现的特征有关。在两个家庭中，CaLM和神经鞘瘤共同发生。分子光谱主要由截短变体组成，表示LoF。这些变体与神经鞘瘤病和隐性NS中发生的变体基本上重叠。功能表征显示加速的蛋白质降解或错误定位，和未能下调MAPK信号。
结论：我们的发现扩大了与LZTR1变异相关的表型变异，which,除了赋予神经鞘瘤病易感性和引起显性和隐性NS，发生在具有孤立的多个CaLMs的个体中。
