Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Hum Mol Genet. 2022 Jul 21;31(14):2307-2316. doi: 10.1093/hmg/ddab366.
Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.
下丘脑错构瘤伴痴笑发作是儿童期耐药性癫痫的明确病因。新的手术技术的发展使得对下丘脑错构瘤组织进行基因组研究成为可能。在少数病例中，这种方法揭示了 GLI3、OFD1 和其他关键 sonic-hedgehog 通路调节因子的致病变异体。 sonic-hedgehog 信号蛋白定位于细胞细胞器初级纤毛。因此，我们探索了这样一种假说，即纤毛基因变异可能是迄今为止尚未解决的散发性下丘脑错构瘤病例的基础。我们对 27 名患者手术切除的下丘脑错构瘤组织和配对的白细胞衍生 DNA 进行了高深度外显子组测序和染色体微阵列分析。我们在显性和双等位基因遗传模型下，同时搜索种系和体细胞变异。在 7 名患者的错构瘤衍生 DNA 中，我们在四个纤毛基因（DYNC2I1、DYNC2H1、IFT140 或 SMO）中的一个中发现了双等位基因（一个种系，一个体细胞）变异。在 8 名患者中，我们在先前确定的下丘脑错构瘤疾病基因 GLI3 或 OFD1 中发现了单个体细胞变异。总体而言，我们为 27 名患者中的 15 名（56%）建立了合理的分子病因。在这里，我们将遗传结构从导致散发性下丘脑错构瘤的显性疾病基因中的单变异扩展到双等位基因（一个种系/一个体细胞）变异，涉及三个新的纤毛基因，并将该疾病重新概念化为纤毛病。
