Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
Technology Center of Prenatal Diagnosis and Genetic Diseases Diagnosis, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
DNA Cell Biol. 2020 Sep;39(9):1685-1690. doi: 10.1089/dna.2020.5359. Epub 2020 Jun 24.
In families with a monogenic disorder, the causal mutation usually cosegregates with the disease phenotype. In rare cases, however, individuals carrying the same mutation within a family may show various phenotypes. This study aimed to analyze the discrepancy between genotype and phenotype in three families with moderate hemophilia A (HA) caused by missense mutation in the gene. Among the 67 noninversion moderate HA families in our cohort, incomplete penetrance was found in three families. In these three families, the grandfathers were asymptomatic, whereas the probands had different clinical phenotypes. Apart from one mutation in the gene (c.1330 G>A) found in one grandfather, only one missense mutation (c.5837A>T, c.6679G>A, and c.6506G>A, in the respective families) in the gene was identified in each proband and their grandfathers. Subsequent Sanger sequencing results combined with bioinformatic analysis indicated that the three missense mutations in the gene were the causative mutations. Our study demonstrated incomplete penetrance of missense mutation within HA families in China. Therefore, genetic counseling and management of such cases need to be reappraised.
在单基因疾病的家族中，致病突变通常与疾病表型共分离。然而，在罕见情况下，家族中携带相同突变的个体可能表现出不同的表型。本研究旨在分析三例由 基因中错义突变引起的中度血友病 A (HA) 家系中基因型与表型的差异。在我们队列的 67 例非倒位中度 HA 家系中，发现有三例存在不完全外显率。在这三个家系中，祖父无症状，而先证者具有不同的临床表型。除了在一位祖父中发现的一个 基因中的突变（c.1330 G>A）外，每个先证者及其祖父中仅发现 基因中的一个错义突变（c.5837A>T、c.6679G>A 和 c.6506G>A，分别在各自的家系中）。随后的 Sanger 测序结果结合生物信息学分析表明， 基因中的三个错义突变是致病突变。我们的研究表明，中国 HA 家系中存在 基因突变的不完全外显率。因此，需要重新评估此类病例的遗传咨询和管理。
