背景:泰萨克斯病(TSD),一种常染色体隐性遗传性神经变性溶酶体贮积病,据报道,在全球范围内,东欧和阿什肯纳齐犹太血统的人群中发病率很高。编码β-己糖胺酶-A的HEXA的α亚基中的突变导致缺乏的酶活性和TSD表型。这项研究是第一个在一组患有婴儿TSD的埃及患者中强调HEXA序列变异谱的研究。
结果:这项研究涉及13名出现婴儿型TSD的埃及婴儿/儿童患者,13名患者中有10名是近亲结婚。13例患者的β-己糖胺酶-A酶活性显着降低,平均活性为3µmol/L/h±1.56。对HEXA编码区和剪接接头进行Sanger测序,在我们的患者中发现了〜62%(8/13)的分子缺陷;六个纯合突变儿童(其中五个是近亲婚姻的产物)和两个患者在杂合基因型中显示了他们的突变等位基因,而其余患者未发现致病突变。调节性基因内突变或del/dup可能是那些未显示相关致病性测序变体的患者或具有突变等位基因杂合基因型的两名患者的分子缺陷的基础。这项研究确定了三本小说,可能与TSD表型相关的致病变异;两个错义,第8外显子c.920A>C(E307A)和c.952C>G(H318D),并且单碱基缺失c.484delG导致移码E162Rfs*37(第Glu162ArgfsTer37)在外显子5。三个复发性致病错义突变;c.1495C>T(R499C),c.1511G>A(R504H),和c.1510C>T(R504C)的外显子13在8例患者中的5例被确定。在50名健康埃及人的DNA中没有检测到这些变异。五个变种,可能是良性的或意义不确定的,S3T,I436V,E506E,和T2T,在我们的研究中检测到外显子1、11、13和1。
结论:对于正确的诊断,遗传咨询,和一级预防,我们的研究强调了下一代测序方法在描述TSD候选患者的分子缺陷方面的重要作用,这些患者在基因检测结果中显示Sanger测序阴性或杂合突变等位基因.有趣的是,3个复发的TSD相关突变聚集在13号染色体上,占本研究中检测到的HEXA突变的38%.这表明外显子13是在患有婴儿TSD的埃及患者中进行测序筛选的第一个候选者。建议进行涉及我们地区人口的较大研究,因此,独特的疾病相关的致病变异可以被识别。
Tay-Sachs disease (TSD), an autosomal recessively inherited neurodegenerative lysosomal storage disease, reported worldwide with a high incidence among population of Eastern European and Ashkenazi Jewish descent. Mutations in the alpha subunit of HEXA that encodes for the β-hexosaminidase-A lead to deficient enzyme activity and TSD phenotype. This study is the first to highlight the HEXA sequence variations spectrum in a cohort of Egyptian patients with infantile TSD.
This study involved 13 Egyptian infant/children patients presented with the infantile form of TSD, ten of the 13 patients were born to consanguineous marriages. β-hexosaminidase-A enzyme activity was markedly reduced in the 13 patients with a mean activity of 3 µmol/L/h ± 1.56. Sanger sequencing of the HEXA\' coding regions and splicing junctions enabled a detection rate of ~ 62% (8/13) in our patients revealing the molecular defects in eight patients; six homozygous-mutant children (five of them were the product of consanguineous marriages) and two patients showed their mutant alleles in heterozygous genotypes, while no disease-causing mutation was identified in the remaining patients. Regulatory intragenic mutations or del/dup may underlie the molecular defect in those patients showing no relevant pathogenic sequencing variants or in the two patients with a heterozygous genotype of the mutant allele. This research identified three novel, likely pathogenic variants in association with the TSD phenotype; two missense, c.920A > C (E307A) and c.952C > G (H318D) in exon 8, and a single base deletion c.484delG causing a frameshift E162Rfs*37 (p.Glu162ArgfsTer37) in exon 5. Three recurrent disease-causing missense mutations; c.1495C > T (R499C), c.1511G > A(R504H), and c.1510C > T(R504C) in exon 13 were identified in five of the eight patients. None of the variants was detected in 50 healthy Egyptians\' DNA. Five variants, likely benign or of uncertain significance, S3T, I436V, E506E, and T2T, in exons 1, 11,13, & 1 were detected in our study.
For the proper diagnostics, genetic counseling, and primary prevention, our study stresses the important role of Next Generation Sequencing approaches in delineating the molecular defect in TSD-candidate patients that showed negative Sanger sequencing or a heterozygous mutant allele in their genetic testing results. Interestingly, the three recurrent TSD associated mutations were clustered on chromosome 13 and accounted for 38% of the HEXA mutations detected in this study. This suggested exon 13 as the first candidate for sequencing screening in Egyptian patients with infantile TSD. Larger studies involving our regional population are recommended, hence unique disease associated pathogenic variations could be identified.