Manjunath V, Thenral S G, Lakshmi B R, Nalini Atchayaram, Bassi A, Karthikeyan K Priya, Piyusha K, Menon R, Malhotra A, Praveena L S, Anjanappa R M, Murugan S M Sakthivel, Polavarapu Kiran, Bardhan Mainak, Preethish-Kumar V, Vengalil Seena, Nashi Saraswati, Sanga S, Acharya M, Raju R, Pai V R, Ramprasad V L, Gupta R
MedGenome Labs Pvt. Ltd., Bangalore, India.
Yenepoya Medical College, Yenepoya (Deemed to be University), Deralakatte, Mangalore, India.
Hum Mutat. 2023 Mar 28;2023:4362273. doi: 10.1155/2023/4362273. eCollection 2023.
The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the , , , and proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins. In this study, we summarized 1,046 LGMD patients for which a precise diagnosis was identified using targeted sequencing. The most frequent phenotypes identified in the patients are LGMDR1 (19.7%), LGMDR4 (19.0%), LGMDR2 (17.5%), and MMD1 (14.5%). Among the reported genes, each of , , and variants was reported in more than 10% of our study cohort. The most common variant p.Thr182Pro was identified in 146 (12.5%) of the LGMD patients, and in 97.9% of these patients, the variant was found to be homozygous. To understand the genetic structure of the patients carrying p.Thr182Pro, we genotyped 68 LGMD patients using a whole genome microarray. Analysis of the array data identified a large ~1 Mb region of homozygosity (ROH) (chr4:51817441-528499552) suggestive of a shared genomic region overlapping the recurrent missense variant and shared across all 68 patients. Haplotype analysis identified 133 marker haplotypes that were present in ~85.3% of the probands as a double allele and absent in all random controls. We also identified 5 markers (rs1910739, rs6852236, rs13122418, rs13353646, and rs6554360) which were present in a significantly higher proportion in the patients compared to random control set ( = 128) and the population database. Of note, admixture analysis was suggestive of greater proportion of West Eurasian/European ancestry as compared to random controls. Haplotype analysis and frequency in the population database indicate a probable event of founder effect. Further systematic study is needed to identify the communities and regions where the p.Thr182Pro variant is observed in higher proportions. After identifying these communities and//or region, a screening program is needed to identify carriers and provide them counselling.
肌聚糖病是常染色体隐性遗传性肢带型肌营养不良症（LGMDs），由编码稳定肌细胞膜的α、β、γ和δ蛋白的基因突变引起。临床表型的特征是儿童期起病的进行性近端肌无力。肌肉活检结果有助于确诊营养不良性改变以及一种或多种肌聚糖蛋白的缺乏。在本研究中，我们总结了1046例通过靶向测序明确诊断的LGMD患者。患者中最常见的表型是LGMDR1（19.7%）、LGMDR4（19.0%）、LGMDR2（17.5%）和MMD1（14.5%）。在所报道的基因中，α、β和γ基因的变异在我们研究队列中的比例均超过10%。最常见的变异p.Thr182Pro在146例（12.5%）LGMD患者中被发现，其中97.9%的患者该变异为纯合子。为了解携带p.Thr182Pro患者的遗传结构，我们使用全基因组微阵列对68例LGMD患者进行了基因分型。阵列数据分析确定了一个大约1 Mb的纯合区域（ROH）（chr4:51817441-528499552），提示存在一个与复发性错义变异重叠且在所有68例患者中共享的基因组区域。单倍型分析确定了133个标记单倍型，约85.3%的先证者以双等位基因形式存在，而在所有随机对照中均不存在。我们还确定了5个标记（rs1910739、rs6852236、rs13122418、rs13353646和rs6554360），与随机对照组（n = 128）和人群数据库相比，这些标记在患者中的比例显著更高。值得注意 的是，混合分析表明与随机对照相比，患者具有更高比例的西欧亚/欧洲血统。单倍型分析和人群数据库中的频率表明可能存在奠基者效应。需要进一步进行系统研究，以确定观察到较高比例p.Thr182Pro变异的社区和地区。在确定这些社区和/或地区后，需要开展筛查项目以识别携带者并为他们提供咨询。
