Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Brain. 2022 Jun 3;145(5):1668-1683. doi: 10.1093/brain/awab327.
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.
STXBP1 中的致病变异是最常见的神经发育障碍的遗传原因之一。然而，STXBP1 相关疾病的表型谱很广，到目前为止，还没有观察到变异类型与临床特征之间的明确相关性。在这里，我们对 534 名 STXBP1 相关疾病患者的临床数据进行了协调，并分析了 19973 个衍生的表型术语，包括以前在科学文献中未报道的 253 名患者的表型。STXBP1 相关疾病的整体表型特征是 95%的患者存在神经发育异常，89%的患者存在癫痫发作，包括局灶性发作癫痫是最常见的癫痫发作类型（47%）。超过 88%的 STXBP1 相关疾病患者的癫痫发作始于生命的第一年，包括 47%的新生儿癫痫发作。携带 STXBP1 蛋白截断变异和缺失的个体（n=261）出现婴儿痉挛症的可能性几乎是两倍，并且表型上比随机预期更为相似。在超过 10 名患者中发现了 5 个具有反复变异的遗传热点，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）。没有一个反复出现的变异与明显的电临床综合征、单一表型特征或总体临床相似性相关，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 STXBP1 相关疾病患者的癫痫发作史，回顾性地在 4433 个时间间隔内每月分配癫痫发作类型和频率，并从电子病历中检索到 251 份抗癫痫药物处方。我们证明了癫痫发作控制的动态模式，以及与特定药物反应的复杂相互作用，特别是在 STXBP1 相关疾病中癫痫发作最明显的第一年。与其他治疗选择相比，促肾上腺皮质激素和苯巴比妥更有可能最初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 相关疾病中多维表型特征谱，以促进未来精准医学方法的发展。
