Mudau M M, Essop F, Krause A
Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
S Afr Med J. 2016 Dec 21;107(1):80-82. doi: 10.7196/SAMJ.2016.v107.i1.10907.
Fukutin-related protein (FKRP) muscular dystrophy is an autosomal recessive disorder caused by mutations in the FKRP gene. The condition is often misdiagnosed as a dystrophinopathy. A previously unreported mutation, c.1100T>C in exon 4 of FKRP, had been identified in homozygous form in two white South African (SA) Afrikaner patients clinically diagnosed with a dystrophinopathy.
To investigate whether the c.1100T>C mutation and the common European FKRP mutation c.826C>A are present in other patients of Afrikaner origin with suspected dystrophinopathy, and whether a founder haplotype exists.
The c.1100T>C mutation was initially tested for using an amplification refractory mutation system technique in 45 white SA Afrikaner patients who had tested negative using multiplex ligation probe amplification screening for exonic deletions/duplications in the dystrophin gene. Sequencing analysis was used to confirm the c.1100T>C mutation and screen for the c.826C>A mutation. Two cohorts (each numbering 100) of Afrikaans and other white controls were screened for the c.1100T>C and c.826C>A mutations, respectively.
Of the 45 patients, 8 patients (17.8%) were homozygous for c.1100T>C, 2 (4.4%) were compound heterozygotes for c.1100T>C and c.826C>A, and 1 (2.2%) was heterozygous for c.1100T>C with a second unidentified mutation. The c.1100T>C mutation was found in 1/100 controls, but no heterozygotes for the c.826C>A mutation were identified. Linked marker analysis for c.1100T>C showed a common haplotype, suggesting a probable founder mutation in the SA Afrikaner population.
FKRP mutations may be relatively common in Afrikaners, and screening should be considered in patients who have a suggestive phenotype and test negative for a dystrophinopathy. This test will be useful for offering diagnostic, carrier and prenatal testing for affected individuals and their families. As FKRP muscular dystrophy is autosomal recessive in inheritance, the implications of a positive diagnosis in a family differ significantly from those of an X-linked dystrophinopathy.
福库汀相关蛋白（FKRP）型肌营养不良症是一种常染色体隐性疾病，由FKRP基因突变引起。该病症常被误诊为肌营养不良蛋白病。在两名临床诊断为肌营养不良蛋白病的南非白人阿非利卡患者中，发现了一种先前未报道的突变，即FKRP基因第4外显子中的c.1100T＞C，呈纯合形式。
调查c.1100T＞C突变以及常见的欧洲FKRP突变c.826C＞A是否存在于其他疑似患有肌营养不良蛋白病的阿非利卡人后裔患者中，以及是否存在奠基者单倍型。
最初采用扩增阻滞突变系统技术，对45名经多重连接探针扩增筛查肌营养不良蛋白基因外显子缺失/重复呈阴性的南非白人阿非利卡患者进行c.1100T＞C突变检测。采用测序分析来确认c.1100T＞C突变并筛查c.826C＞A突变。分别对两组各100名阿非利卡人和其他白人对照进行c.1100T＞C和c.826C＞A突变筛查。
在这45名患者中，8名患者（17.8%）为c.1100T＞C纯合子，2名患者（4.4%）为c.1100T＞C和c.826C＞A的复合杂合子，1名患者（2.2%）为c.1100T＞C杂合子且伴有另一种未识别的突变。在1/100的对照中发现了c.1100T＞C突变，但未鉴定出c.826C＞A突变的杂合子。对c.1100T＞C的连锁标记分析显示存在一种常见单倍型，提示在南非阿非利卡人群中可能存在奠基者突变。
FKRP突变在阿非利卡人中可能相对常见，对于具有提示性表型且肌营养不良蛋白病检测呈阴性的患者应考虑进行筛查。该检测对于为受影响个体及其家庭提供诊断、携带者和产前检测将很有用。由于FKRP型肌营养不良症为常染色体隐性遗传，家族中阳性诊断的意义与X连锁肌营养不良蛋白病有显著差异。
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