新发致病变异患者的基因型-表型相关性
Genotype-phenotype correlations in patients with de novo pathogenic variants.
作者信息
Malerba Federica, Alberini Giulio, Balagura Ganna, Marchese Francesca, Amadori Elisabetta, Riva Antonella, Vari Maria Stella, Gennaro Elena, Madia Francesca, Salpietro Vincenzo, Angriman Marco, Giordano Lucio, Accorsi Patrizia, Trivisano Marina, Specchio Nicola, Russo Angelo, Gobbi Giuseppe, Raviglione Federico, Pisano Tiziana, Marini Carla, Mancardi Maria M, Nobili Lino, Freri Elena, Castellotti Barbara, Capovilla Giuseppe, Coppola Antonietta, Verrotti Alberto, Martelli Paola, Miceli Francesco, Maragliano Luca, Benfenati Fabio, Cilio Maria R, Johannesen Kathrine M, Møller Rikke S, Ceulemans Berten, Minetti Carlo, Weckhuysen Sarah, Zara Federico, Taglialatela Maurizio, Striano Pasquale
机构信息
Department of Neurosciences (F. Malerba, G.B., E.A., A. Riva, V.S., L.N., C. Minetti, F.Z., P.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova; Pediatric Neurology and Muscular Diseases Unit (F. Malerba, G.B., F. Marchese, E.A., A. Riva, M.S.V., V.S., C. Minetti, P.S.), IRCCS Istituto G. Gaslini; Center for Synaptic Neuroscience and Technology (NSYN@UniGe) (G.A., L.M., F.B.), Istituto Italiano di Tecnologia; Department of Experimental Medicine (G.A.), Università degli Studi di Genova; Laboratory of Human Genetics (E.G.); Unit of Medical Genetics (F. Madia, F.Z.), IRCCS Istituto G. Gaslini, Genova, Italy; Child Neurology and Neurorehabilitation Unit (M.A.), Department of Pediatrics, Central Hospital of Bolzano, Bolzano; Child Neurology and Psychiatry Unit (L.G., P.A., P.M.), ASST Spedali Civili, Brescia; Neurology Unit (M. Trivisano, N.S.), Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Roma; Child Neurology Unit (A. Russo, G.G.), IRCCS, Institute of Neurological Sciences of Bologna; Child Neuropsychiatry Unit (F.R.), U.O.N.P.I.A. ASST-Rhodense, Rho, Milano; Neurology Unit and Laboratories (T.P.), A. Meyer Children's Hospital, Firenze; Child Neurology and Psychiatric Unit (C. Marini), Pediatric Hospital G. Salesi, United Hospital of Ancona; Child Neuropsychiatry Unit (M.M.M., L.N.), IRCCS Istituto G. Gaslini, Genova; Department of Pediatric Neuroscience (E.F.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Genetics of Neurodegenerative and Metabolic Diseases (B. Castellotti), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; Department of Child Neuropsychiatry (G.C.), Epilepsy Center, C. Poma Hospital, Mantova; Fondazione Poliambulanza Brescia (G.C.); Epilepsy Center (A.C.), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; Department of Pediatrics (A.V.), University of Perugia; Section of Pharmacology (F. Miceli, M. Taglialatela), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; IRCCS Ospedale Policlinico San Martino (L.M., F.B.), Genova, Italy; Division of Pediatric Neurology (M.R.C.), Saint-Luc University Hospital, and Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Center Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense, Denmark; Department of Neurology (B. Ceulemans, S.W.), University Hospital Antwerp; Applied & Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp, Belgium; and Department of Life and Environmental Sciences (L.M.), Polytechnic University of Marche, Ancona, Italy.
出版信息
Neurol Genet. 2020 Nov 30;6(6):e528. doi: 10.1212/NXG.0000000000000528. eCollection 2020 Dec.
OBJECTIVE
Early identification of de novo variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo pathogenic variants to dissect genotype-phenotype correlations.
METHODS
Patients with de novo pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.
RESULTS
We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.
CONCLUSIONS
We highlight the complexity of variant interpretation to assess the impact of a class of de novo mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.
目的
早期识别癫痫患者的新生变异对优化治疗的预后问题具有重要意义。我们分析了一组携带新生致病变异患者的临床和遗传信息，以剖析基因型与表型的相关性。
方法
从意大利、丹麦和比利时识别出携带新生致病变异的患者。还使用同源建模生成了原子分辨率的Kv7.2结构，以定位这些变异。
结果
我们纳入了34例患者，平均年龄4.7岁。癫痫发作的中位起病时间为2天，主要为伴有自主神经症状的局灶性发作。22例患者（65%）在平均1.2岁时无癫痫发作。超过一半的患者（17/32）表现出重度/极重度智力残疾；然而，其中4例（13%）认知结果正常。共识别出28种新生致病变异，大多数为错义变异（25/28），且聚集在蛋白质的保守区域；6种变异重复出现，7种为新变异。我们未发现携带错义变异患者的变异位置与癫痫发作缓解或认知结果之间存在关联。此外，重复出现的变异与重叠的癫痫特征相关，但在智力结果方面也有不同的演变。
结论
我们强调了变异解读的复杂性，以评估一类新生突变的影响。可能涉及遗传修饰因子，但需要开发成功解决每个单一突变影响的研究范式。
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