Jalali-Sefid-Dashti Mahjoubeh, Nel Melissa, Heckmann Jeannine M, Gamieldien Junaid
South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, 7535, South Africa.
Division of Neurology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
BMC Med Genet. 2018 Jun 7;19(1):95. doi: 10.1186/s12881-018-0613-x.
We investigated a South African family of admixed ancestry in which the first generation (G1) developed insidious progressive distal to proximal weakness in their twenties, while their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. Our aim was to identify deleterious mutations that segregate with the affected individuals in this family.
Exome sequencing was performed on five cases, which included three affected G1 siblings and two pauci-symptomatic G2 offspring. As controls we included an unaffected G1 sibling and a spouse of one of the G1 affected individuals. Homozygous or potentially compound heterozygous variants that were predicted to be functional and segregated with the affected G1 siblings, were further evaluated. Additionally, we considered variants in all genes segregating exclusively with the affected (G1) and pauci-symptomatic (G2) individuals to address the possibility of a pseudo-autosomal dominant inheritance pattern in this family.
All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF (dysferlin) mutation, with their asymptomatic sibling and both pauci-symptomatic G2 offspring carrying only a single mutant allele. Sanger sequencing confirmed segregation of the variant. No additional potentially contributing variant was found in the DYSF or any other relevant gene in the pauci-symptomatic carriers.
Our finding of a truncating dysferlin mutation confirmed dysferlinopathy in this family and we propose that the single mutant allele is the primary contributor to the neuromuscular symptoms seen in the second-generation pauci-symptomatic carriers.
我们调查了一个具有混合血统的南非家庭，其中第一代（G1）在二十多岁时出现了从远端到近端的隐匿性进行性肌无力，而他们的后代（G2）自青春期以来经历了严重的意外性肌痛和痉挛症状。我们的目的是鉴定与该家族中受影响个体共分离的有害突变。
对五例个体进行了外显子组测序，其中包括三名受影响的G1同胞和两名症状轻微的G2后代。作为对照，我们纳入了一名未受影响的G1同胞和一名G1受影响个体的配偶。对预测具有功能且与受影响的G1同胞共分离的纯合或潜在复合杂合变异进行了进一步评估。此外，我们考虑了所有仅与受影响的（G1）和症状轻微的（G2）个体共分离的基因中的变异，以探讨该家族中假常染色体显性遗传模式的可能性。
所有受影响的G1个体均为一种新的截短型p.Tyr1433Ter DYSF（dysferlin）突变的纯合子，其无症状的同胞和两名症状轻微的G2后代仅携带一个突变等位基因。桑格测序证实了该变异的共分离。在症状轻微的携带者中，未在DYSF或任何其他相关基因中发现其他可能起作用的变异。
我们发现的截短型dysferlin突变证实了该家族存在dysferlinopathy，并且我们提出单个突变等位基因是第二代症状轻微携带者中所见神经肌肉症状的主要原因。
