Table_1_Utility of ACMG classification to support interpretation of molecular genetic test results in patients with factor VII deficiency.pdf

BackgroundThe American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have introduced an internationally shared framework for variant classification in genetic disorders. FVII deficiency is a rare inherited autosomal recessive bleeding disorder with sparse data concerning ACMG classification.
MethodsTo develop an approach which may improve the utility of molecular genetic test results, 129 patients with FVII deficiency were retrospectively assigned to six subgroups for exploratory analysis: F7 gene wildtype (group 1), ACMG 1 (benign variant) or ACMG 2 (likely benign variant), only (group 2), ACMG 3 (variant of uncertain significance) ± ACMG 1–2 heterozygous or not classified variant (group 3), ACMG 4 (likely pathogenic variant), or ACMG 5 (pathogenic variant) single heterozygous ± ACMG 1–3 single heterozygous (group 4), ACMG 4–5 homozygous or ≥2 ACMG 4–5 heterozygous or ≥1 ACMG 4–5 heterozygous plus either ACMG 1 c.1238G>A modifying variant homozygous or ≥2 ACMG 1–3 (group 5), FVII deficiency and another bleeding disorder (group 6).
ResultsEleven of 31 patients (35.5%) in group 5 had abnormal ISTH-BS (n = 7) and/or history of substitution with recombinant factor VIIa (n = 5) versus 4 of 80 patients (5.0%, n = 1 abnormal ISTH-BS, n = 3 substitution) in groups 1 (n = 2/22), 2 (n = 1/29), 3 (n = 0/9), and 4 (n = 1/20). Four of 18 patients (22.2%) with FVII deficiency and another bleeding disorder (group 6) had an abnormal ISTH-BS (n = 2) and/or history of substitution with recombinant factor VIIa (n = 3).
ConclusionPatients with a homozygous ACMG 4–5 variant or with specific combinations of heterozygous ACMG 4–5 ± ACMG 1–3 variants exhibited a high-risk bleeding phenotype in contrast to the remaining patients without another bleeding disorder. This result may serve as a basis to develop a genotype/phenotype prediction model in future studies.

背景 美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）与美国分子病理学会（Association for Molecular Pathology, AMP）已推出一套用于遗传性疾病变异分类的国际通用框架。凝血因子VII（FVII）缺乏症是一种罕见的遗传性常染色体隐性出血性疾病，目前关于其ACMG分类的相关数据仍较为匮乏。
方法 为开发可提升分子遗传检测结果实用性的分析方案，本研究对129例凝血因子VII缺乏症患者进行回顾性分组，共分为6个亚组开展探索性分析：第1组为F7基因野生型；第2组仅携带ACMG 1类（良性变异）或ACMG 2类（可能良性变异）；第3组为ACMG 3类（意义未明变异）伴或不伴ACMG 1-2类杂合变异或未分类变异；第4组为ACMG 4类（可能致病性变异）或ACMG 5类（致病性变异）单杂合，伴或不伴ACMG 1-3类单杂合；第5组为ACMG 4-5类纯合变异、≥2个ACMG 4-5类杂合变异，或≥1个ACMG 4-5类杂合变异联合ACMG 1类c.1238G>A修饰性变异纯合或≥2个ACMG 1-3类变异；第6组为凝血因子VII缺乏症合并其他出血性疾病。
结果 第5组的31例患者中，有11例（35.5%）出现ISTH-BS评分异常（n=7）和/或有重组凝血因子VIIa替代治疗史（n=5）；而第1、2、3、4组共80例患者中仅4例（5.0%，其中1例ISTH-BS评分异常、3例有替代治疗史）出现上述表现，其中第1组2/22、第2组1/29、第3组0/9、第4组1/20。合并其他出血性疾病的第6组18例患者中，有4例（22.2%）出现ISTH-BS评分异常（n=2）和/或有重组凝血因子VIIa替代治疗史（n=3）。
结论 携带ACMG 4-5类纯合变异，或携带ACMG 4-5类与ACMG 1-3类杂合变异的特定组合的患者，相较于未合并其他出血性疾病的其余患者，呈现出高风险出血表型。该研究结果可为未来开展基因型/表型预测模型的研发提供依据。