Frolov Andrey, D'sa Elizabeth, Henderson Camille, Guzman Miguel A, Hayat Ghazala, Martin John R
Department of Surgery - Center for Anatomical Science and Education, Saint Louis University School of Medicine, St. Louis, USA.
Department of Pathology, Saint Louis University School of Medicine, St. Louis, USA.
Cureus. 2024 Dec 19;16(12):e76027. doi: 10.7759/cureus.76027. eCollection 2024 Dec.
A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the gene. mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic and variants, warranting a closer look at their potentially important role in fALS as genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.
肌萎缩侧索硬化症（ALS）显著多样的临床表现，即使在研究最为充分的家族性形式中，仍持续阻碍着目前开发有效疾病修饰药物以治愈这种快速进展的致命性神经肌肉疾病的努力。我们之前已经表明，散发性ALS（sALS）的临床异质性至少部分可以通过其多基因性质以及与非ALS神经疾病相关的突变基因和已知介导ALS相关病理的基因的存在来解释。我们假设类似的遗传框架也可能存在于家族性ALS（fALS）患者中。为了验证这一假设，我们对一名患有fALS且基因发生突变的个体进行了死后基因筛查。突变具有高度外显率，存在于大多数fALS患者中。在美国加利福尼亚州圣地亚哥的Illumina平台上，通过全外显子组测序（WES）进行下一代测序（NGS）基因筛查，随后检查各自罕见的（次要等位基因频率（MAF）≤0.01）病理性/有害遗传变异，其结果与我们关于fALS中存在复杂遗传框架的假设一致。当对低频（0.01 < MAF < 0.05）病理性/有害遗传变异与低频双等位基因和变异进行分析时，确定了该遗传框架的其他成员，这使得有必要更仔细地研究它们作为遗传修饰因子在fALS中的潜在重要作用，以及它们与神经肌肉疾病/ALS和癌症的联系。因此，除了目前使用标准ALS相关基因面板进行的基因筛查外，通过WES进行补充筛查对于开发ALS患者的个性化治疗以及寻找各自有效的疾病修饰药物可能非常有益。
