Mosaad Rehab, El-Kamah Ghada, Eid Maha, Amr Khalda
Molecular Genetics and Enzymology Dpt., Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Clinical Genetics Dpt., Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
J Genet Eng Biotechnol. 2024 Dec;22(4):100435. doi: 10.1016/j.jgeb.2024.100435. Epub 2024 Nov 8.
Fanconi anemia is a genetically heterogeneous recessive disorder distinguished by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and disturbed DNA repair. To date, Fanconi anemia complementation group (FANC) includes 23 FANC genes identified of which, FANCA gene is the most commonly mutated. The mutation spectrum of the FANCA gene is highly heterogeneous with large intragenic deletions due to Alu elements-mediated recombination. The study aimed to identify different deletion mutations on FANCA gene in Egyptian Fanconi anemia patients by multiplex ligation-dependent probe amplification (MLPA) technique to define the spectrum of FA molecular pathology as a step for disease control. The study included 80 FA patients (36 females and 44 males) whose ages ranged from 4 months to 17 years descending from unrelated consanguineous families referred to the Hereditary Blood Disorders Clinic, National Research Centre (NRC), Egypt. Patients were diagnosed with classical clinical presentation of FA and were confirmed by chromosomal breakage using Diepoxybutane (DEB).
The common clinical presentation in our FA patients were the presence of café au lait spots with hyperpigmentation in 65/80 (81%) followed by skeletal defects in 40/80 (50%). MLPA revealed a total of five different intragenic homozygous deletions of FANCA gene in 16 /80 (20%) patients, among them two deletion patterns were novel.
Molecular analysis using MLPA could detect pathogenic mutations in 20% of FA patients, our study generated considerable data on causative mutations that was used for genetic counseling and prenatal diagnosis.
范可尼贫血是一种基因异质性隐性疾病，其特征为细胞遗传不稳定性、对DNA交联剂高度敏感、染色体断裂增加以及DNA修复紊乱。迄今为止，范可尼贫血互补组（FANC）包括已鉴定的23个FANC基因，其中FANCA基因是最常发生突变的。FANCA基因的突变谱高度异质，存在由于Alu元件介导的重组导致的大的基因内缺失。本研究旨在通过多重连接依赖探针扩增（MLPA）技术鉴定埃及范可尼贫血患者FANCA基因的不同缺失突变，以确定范可尼贫血分子病理学谱，作为疾病控制的一个步骤。该研究纳入了80例范可尼贫血患者（36例女性和44例男性），年龄范围为4个月至17岁，来自转诊至埃及国家研究中心（NRC）遗传性血液疾病诊所的无血缘关系的近亲家庭。患者根据范可尼贫血的典型临床表现进行诊断，并通过使用二环氧丁烷（DEB）的染色体断裂进行确认。
我们的范可尼贫血患者的常见临床表现为65/80（81%）出现咖啡牛奶斑伴色素沉着，其次是40/80（50%）出现骨骼缺陷。MLPA显示16/80（20%）的患者中共有5种不同的FANCA基因纯合子基因内缺失，其中两种缺失模式是新发现的。
使用MLPA进行分子分析可在20%的范可尼贫血患者中检测到致病突变，我们的研究生成了大量关于致病突变的数据，可用于遗传咨询和产前诊断。
