Does Parent of Origin Matter? Methylation Studies Should be Performed on Patients with Multiple Copies of the Prader-Willi/Angelman Syndrome Critical Region
Does Parent of Origin Matter? Methylation Studies Should be Performed on Patients with Multiple Copies of the Prader-Willi/Angelman Syndrome Critical Region
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DOI：
10.1002/ajmg.a.36663
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发表时间：
2014-10-01
影响因子：
2
通讯作者：
Hoppman, Nicole
中科院分区：
文献类型：
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作者：
Aypar, Umut;Brodersen, Pamela R.;Hoppman, Nicole
15q11.2-q13缺失会导致Prader-Willi综合征(PWS)或Angelman综合征(AS)，这取决于起源的父母。PWS/AS关键区重复(PWASCR)也被报道与发育迟缓和自闭症有关，而且已经表明它们也显示出父母起源的效应。人们普遍认为母体复制是致病的。然而，关于父亲复制的致病性，有相互矛盾的证据。我们用阵列比较基因组杂交技术鉴定了35例获得PWASCR的患者。进行甲基化测试以确定额外拷贝的来源亲本。在35例中，22例有额外标记的15号染色体(SMC15)，12例有串联重复，1例有串联三倍体。只有一名患者有父系重复；这名患者没有典型的母系重复PWASCR患者的特征。其中三位母亲有串联复制(两位来自父亲，一位来自母亲)。虽然两名父亲重复的母亲中有一人没有自闭症，但另一人有学习障碍和抑郁症。根据我们的数据，我们得出结论，SMC15几乎完全是母系起源的，并导致异常表型。当根据异常表型确定串联复制/三联体时，通常是母系起源；然而，也发现了父系起源的串联复制。因此，我们建议对串联复制/三联体病例进行甲基化检测，因为父亲获得的致病性尚不确定。(C)2014年威利期刊公司。
Deletion of 15q11.2-q13 results in either Prader-Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region(PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent-of-origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain. (C) 2014 Wiley Periodicals, Inc.