PDF(Pubmed)
Abstract：
Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility.
摘要：
非综合征性神经胶质瘤家族聚集的诱发因素仍有待发现。在四个患有脑肿瘤的芬兰家庭中进行全外显子组测序以鉴定罕见的易感变体。使用靶向测序对19个患有脑肿瘤的芬兰家族中总共417个检测到的外显子组变体和102个先前报道的神经胶质瘤相关变体进行了进一步的基因分型。在GALNT13、MYO10和AR中鉴定出罕见的破坏性变体。两个家族在GALNT13上带有c.553C>T（R185C）或c.1214T>A（L405Q）。变体c.553C>T位于GALNT13的底物结合位点上。ARc.2180G>T（R727L），它位于AR的配体结合域上，在两个家庭中被发现，其中一个还带有GALNT13变体。在两个家族中检测到MYO10c.4448A>G（N1483S），在一个家族中检测到c.1511C>T（A504V）变异。两种变体都位于与丝足虫形成中的MYO10活性相关的功能域上。此外,6个家庭的受影响病例携带CCDC26中已知的神经胶质瘤风险变异rs55705857和低风险神经胶质瘤变异。这些新发现表明芬兰家族性神经胶质瘤的多基因遗传，并增加了我们对家族性神经胶质瘤易感性的遗传贡献的理解。
