The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.
The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.
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DOI：
10.1038/gim.2016.53
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发表时间：
2017-01
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最近报道，位于 Prader-Willi 关键区域 15q11-13 的母系印记、父系表达基因 MAGEL2 的截短突变会导致 Schaaf-Yang 综合征，这是一种类似 Prader-Willi 的疾病，表现为发育迟缓/智力障碍、肌张力低下、喂养困难和自闭症谱系障碍。所报道的变异与患者表型之间的因果关系受到质疑，因为 MAGEL2 全基因缺失似乎几乎不会导致临床表型。在这里，我们报告了来自 14 个家庭的 18 名新患有 Schaaf-Yang 综合征的个体，其中一个家庭有 3 名个体被发现受到 MAGEL2 截短变体的影响，11 名个体受到临床影响，但未经分子检测，以及一名出现症状前胎儿兄弟姐妹携带致病性 MAGEL2 变异。所有病例均存在 MAGEL2 截短突变，并且 c.1990-1996 核苷酸作为突变热点出现，其中 10 名个体和一名胎儿携带 c.1996dupC (p.Q666fs) 突变，两名胎儿携带 c.1996delC (p.Q666fs) 突变。 Schaaf-Yang 综合征的表型范围从胎儿运动不能到患有神经行为疾病和小指关节挛缩的个体。这项研究为 MAGEL2 父系等位基因截短突变的致病性提供了强有力的证据，完善了相关的临床表型，并强调了对受影响家庭遗传咨询的影响。
Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease, manifesting developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole gene deletions appear to cause little to no clinical phenotype. Here we report a total of 18 new individuals with Schaaf-Yang syndrome from 14 families, including one family with three individuals found to be affected with a truncating variant of MAGEL2, 11 individuals clinically affected, but not tested molecularly, and a presymptomatic fetal sibling with carrying the pathogenic MAGEL2 variant. All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and one fetus harboring a c.1996dupC (p.Q666fs) mutation and two fetuses harboring a c.1996delC (p.Q666fs). The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to individuals with neurobehavioral disease and contractures of the small finger joints. This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling of affected families.
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