Assessing the landscape of STXBP1-related disorders in 534 individuals.
Assessing the landscape of STXBP1-related disorders in 534 individuals.
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DOI：
10.1093/brain/awab327
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发表时间：
2022-06-03
期刊：
影响因子：
14.5
通讯作者：
Helbig, Ingo
中科院分区：
文献类型：
--
作者：
Xian, Julie;Parthasarathy, Shridhar;Ruggiero, Sarah M.;Balagura, Ganna;Fitch, Eryn;Helbig, Katherine;Gan, Jing;Ganesan, Shiva;Kaufman, Michael C.;Ellis, Colin A.;Lewis-Smith, David;Galer, Peter;Cunningham, Kristin;O'Brien, Margaret;Cosico, Mahgenn;Baker, Kate;Darling, Alejandra;de Goes, Fernanda Veiga;El Achkar, Christelle M.;Doering, Jan Henje;Furia, Francesca;Garcia-Cazorla, Angeles;Gardella, Elena;Geertjens, Lisa;Klein, Courtney;Kolesnik-Taylor, Anna;Lammertse, Hanna;Lee, Jeehun;Mackie, Alexandra;Misra-Isrie, Mala;Olson, Heather;Sexton, Emma;Sheidley, Beth;Smith, Lacey;Sotero, Luiza;Stamberger, Hannah;Syrbe, Steffen;Thalwitzer, Kim Marie;van Berkel, Annemiek;van Haelst, Mieke;Yuskaitis, Christopher;Weckhuysen, Sarah;Prosser, Ben;Rigby, Charlene Son;Demarest, Scott;Pierce, Samuel;Zhang, Yuehua;Moller, Rikke S.;Bruining, Hilgo;Poduri, Annapurna;Zara, Federico;Verhage, Matthijs;Striano, Pasquale;Helbig, Ingo
STXBP1 的致病变异是神经发育障碍最常见的遗传原因之一。然而，STXBP1相关疾病的表型谱很广泛，迄今为止尚未观察到变异类型与临床特征之间的明确相关性。在这里，我们协调了 534 名患有 STXBP1 相关疾病的个体的临床数据，并分析了 19 973 个派生的表型术语，包括先前在科学文献中未报道的 253 名个体的表型。 STXBP1 相关疾病的总体表型特征是 95% 的个体出现神经发育异常，89% 的个体出现癫痫发作，其中局灶性癫痫发作是最常见的癫痫发作类型 (47%)。超过 88% 的 STXBP1 相关疾病患者在一岁内出现癫痫发作，其中 47% 的新生儿出现癫痫发作。 STXBP1 中具有蛋白质截短变异和缺失的个体 (n = 261) 出现 West 综合征的可能性几乎是两倍，并且表型比偶然预期的更加相似。在 10 多个个体中鉴定出 5 个具有复发性变异的遗传热点，包括 p.Arg406Cys/His (n = 40)、p.Arg292Cys/His/Leu/Pro (n = 30)、p.Arg551Cys/Gly/His/Leu (n = 24)、p.Pro139Leu (n = 12) 和p.Arg190Trp (n = 11)。没有一个复发性变异与不同的电临床综合征、单一表型特征显着相关，或者表现出总体临床相似性，这表明STXBP1相关疾病的基线变异性太高，无法出现离散的表型亚组。然后，我们详细重建了 62 名患有 STXBP1 相关疾病的个体的癫痫病史，在 4433 个时间间隔内每月回顾性分配癫痫发作类型和癫痫发作频率，并从电子病历中检索了 251 个抗癫痫药物处方。我们展示了癫痫控制的动态模式以及与特定药物反应的复杂相互作用，特别是在生命的第一年，此时 STXBP1 相关疾病的癫痫发作最为突出。与其他治疗方案相比，促肾上腺皮质激素和苯巴比妥最初更有可能降低婴儿痉挛症和局灶性癫痫发作的频率，而生酮饮食在维持无癫痫发作方面最有效。总之，我们展示了如何使用计算表型框架评估 STXBP1 相关疾病的表型特征的多维谱，以促进未来精准医学方法的发展。西安等人。报告迄今为止对 STXBP1 相关疾病最大规模的临床分析结果。该研究将 534 名个体的临床数据映射到计算表型框架，描述了 STXBP1 相关疾病的复杂基因型-表型景观，扩展了预后和机制视野。
Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches. Xian et al. report findings from the largest clinical analysis of STXBP1-related disorders to date. Mapping the clinical data of 534 individuals to a computational phenotype framework, the study describes the complex genotype–phenotype landscape of STXBP1-related disorders, extending prognostic and mechanistic horizons.
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影响因子：
2.6
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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影响因子：
14.9
作者：
Köhler S;Gargano M;Matentzoglu N;Carmody LC;Lewis-Smith D;Vasilevsky NA;Danis D;Balagura G;Baynam G;Brower AM;Callahan TJ;Chute CG;Est JL;Galer PD;Ganesan S;Griese M;Haimel M;Pazmandi J;Hanauer M;Harris NL;Hartnett MJ;Hastreiter M;Hauck F;He Y;Jeske T;Kearney H;Kindle G;Klein C;Knoflach K;Krause R;Lagorce D;McMurry JA;Miller JA;Munoz-Torres MC;Peters RL;Rapp CK;Rath AM;Rind SA;Rosenberg AZ;Segal MM;Seidel MG;Smedley D;Talmy T;Thomas Y;Wiafe SA;Xian J;Yüksel Z;Helbig I;Mungall CJ;Haendel MA;Robinson PN
通讯作者：
Robinson PN
DOI：
10.1038/s41436-020-0923-1
发表时间：
2020-12
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Ganesan S;Galer PD;Helbig KL;McKeown SE;O'Brien M;Gonzalez AK;Felmeister AS;Khankhanian P;Ellis CA;Helbig I
通讯作者：
Helbig I