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Abstract：
Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5\' end and 3\' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3\' end processing of precursor-U8.
摘要：
编码小核仁RNAU8的SNORD118中的双等位基因突变引起伴有钙化和囊肿(LCC)的白质脑病。鉴于难以解释非蛋白质编码基因中变体的功能后果，和对照中SNORD118的高等位基因多态性，我们着手提供在一组LCC患者中观察到的分子病理学和临床谱的描述.我们确定了来自56个家庭的64名受影响的个体。演讲年龄从3周到67岁不等，8例患者在40岁后发病。十名患者死亡。我们记录了44个不同的，可能致病，SNORD118中的变体。56位先证者中有52位是复合杂合子，只有三个家庭有父母血缘关系。56个先证者中的49个是杂合的（46个）或纯合的（3个），其突变涉及七个核苷酸之一，该核苷酸促进前体U8的5'末端和3'延伸之间的新型分子内相互作用。没有明显的基因型-表型相关性来解释发病年龄的显着变异性。在斑马鱼模型中补充最近发表的功能分析，这些数据表明，LCC最常发生由于组合严重和温和的突变，后者主要影响前体U8的3'端加工。
