Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
Muscle Nerve. 2013 Jun;47(6):931-7. doi: 10.1002/mus.23763. Epub 2013 May 11.
Clinical heterogeneity of limb-girdle muscular dystrophies (LGMDs, 24 known subtypes), which includes overlapping phenotypes and varying ages of onset and morbidity, adds complexity to clinical and molecular diagnoses.
To diagnose LGMD subtype, protein analysis, using immunohistochemistry (IHC) and immunoblotting, was followed by gene sequencing through a panel approach (simultaneous sequencing of known LGMD genes) in 9 patients from unrelated families of the Indian Agarwal community. Haplotype studies were performed by targeted SNP genotyping to establish mutation segregation.
We identified 2 founder mutations in CAPN3, a missense (c.2338G>C; p.D780H) and a splice-site (c.2099-1G>T) mutation, on 2 different haplotype backgrounds. The patients were either heterozygous for both or homozygous for either of these mutations.
Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD.
肢带型肌营养不良症（LGMD，24 种已知亚型）的临床表现存在异质性，包括重叠的表型以及发病年龄和发病率的不同，这给临床和分子诊断带来了复杂性。
为了诊断 LGMD 亚型，我们对 9 名来自印度 Agarwal 社区无亲缘关系家庭的患者进行了蛋白分析，使用免疫组织化学（IHC）和免疫印迹法，然后通过面板方法（同时对已知的 LGMD 基因进行测序）进行基因测序。通过靶向 SNP 基因分型进行单体型研究，以确定突变的分离。
我们在 CAPN3 中发现了 2 个 founder 突变，一个错义突变（c.2338G>C；p.D780H）和一个剪接位点突变（c.2099-1G>T），位于 2 个不同的单体型背景上。这些患者要么同时携带这两种突变中的一种，要么是这两种突变中的任意一种的纯合子。
这些 founder 突变至少在某些特定人群中具有直接的临床应用价值。临床上可用的基因panel 可能为 LGMD 等异质性疾病提供明确的分子诊断。
