PURPOSE Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. METHODS Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. RESULTS We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. CONCLUSION In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.

中文翻译：

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参与胆固醇生物合成的羊毛甾醇合酶基因 LSS 中的双等位基因致病变异导致智障脱发，这是一种罕见的隐性神经外胚层综合征。

目的 羊毛甾醇合酶 (LSS) 基因最初是在患有广泛先天性白内障的家庭中描述的。最近，一项研究强调了与单纯性少毛症相关的 LSS。我们将 LSS 的表型谱扩展到一种隐性神经外胚层综合征，以前称为智力迟钝 (APMR) 综合征的脱发。它是一种罕见的常染色体隐性遗传病，以少毛症和智力障碍 (ID) 或发育迟缓 (DD) 为特征，通常与早发性癫痫和其他皮肤病学特征相关。方法 通过一项多中心国际合作研究，我们通过外显子组测序或 LSS Sanger 测序鉴定了 APMR 个体的 LSS 致病变异。通过转录分析和小基因分析评估剪接缺陷。结果 我们报告了来自 6 个不相关家族的 10 个 APMR 个体，在 LSS 中具有双等位基因变异。我们还确定了一个受影响的个体，该个体在 LSS 中有一个罕见的变体和一个等位基因失衡，表明第二个事件。在已识别的变体中，两个是截断变体，七个是错义变体，两个是剪接变体。胆固醇及其前体的量化并没有显示出明显的不平衡。结论在胆固醇生物合成途径中，羊毛甾醇合酶导致(S)-2,3-氧化角鲨烯环化为羊毛甾醇。我们的数据表明 LSS 是导致罕见的隐性神经外胚层综合征的主要基因。在已识别的变体中，两个是截断变体，七个是错义变体，两个是剪接变体。胆固醇及其前体的量化并没有显示出明显的不平衡。结论在胆固醇生物合成途径中，羊毛甾醇合酶导致(S)-2,3-氧化角鲨烯环化为羊毛甾醇。我们的数据表明 LSS 是导致罕见的隐性神经外胚层综合征的主要基因。在已识别的变体中，两个是截断变体，七个是错义变体，两个是剪接变体。胆固醇及其前体的量化并没有显示出明显的不平衡。结论在胆固醇生物合成途径中，羊毛甾醇合酶导致(S)-2,3-氧化角鲨烯环化为羊毛甾醇。我们的数据表明 LSS 是导致罕见的隐性神经外胚层综合征的主要基因。