Background

Familial hypercholesterolemia (FH), an autosomal codominant disorder characterized by very high low-density lipoprotein cholesterol, is strongly associated with premature coronary artery disease.

Objectives

Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives, and cascade screening in their relatives.

Methods

Potential cases of FH (n = 100) were identified by criteria adapted for the Indian population from Dutch Lipid Clinic Network criteria. Pathogenic variants were analyzed in LDLR, APOB 100 (exons 26 and 29), PCSK9, and APOE genes using Sanger sequencing and multiplex ligation-dependent probe amplification technique. Cases in whom there were no pathogenic variants were tested by next-generation sequencing using a targeted panel of genes.

Results

Thirty-eight pathogenic variants were identified in 47 of 100 unrelated probands. Of these variants, 33 were identified in LDLR, 3 in APOB, and 2 in PCSK9 genes. Ten pathogenic variants were novel. Mutations were detected in 91.4% of those subjects classified as definite, 40% as probable, and in 18.8% as possible FH cases based on modified Dutch Lipid Clinic Network criteria. A likely founder mutation in intron 10 (c.1587-1G>A) of LDLR gene was observed in 6 North Indian families. The conventional pathogenic variants in APOB and PCSK9 genes and those previously reported in LDLR gene among Asian Indians were not detected in this cohort.

Conclusion

This study demonstrates genetic heterogeneity of FH in India. The variants observed were different from those described in Western populations. Next-generation sequencing technology helped identify new mutations in APOB gene, suggesting that in less-studied populations, it is better to sequence the whole gene rather than test for specific mutations.

中文翻译：

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亚洲印第安人家族性高胆固醇血症的遗传分析：单中心研究。

背景

家族性高胆固醇血症（FH）是一种常染色体显性遗传疾病，其特征是低密度脂蛋白胆固醇非常高，与冠状动脉早发疾病密切相关。

目标

尽管该族裔占世界人口的很大比例，但对亚洲印第安人中FH的分子景观研究尚未深入。这些人群中的突变知识对于识别受FH影响的人，挽救他们的生命以及对其亲属进行级联筛查非常有用。

方法

潜在的FH病例（n = 100）是根据荷兰血脂临床网络标准通过适合印度人口的标准确定的。使用Sanger测序和依赖多重连接的探针扩增技术对LDLR，APOB 100（第26和29号外显子），PCSK9和APOE基因的致病变异进行了分析。使用靶向基因组通过下一代测序测试了没有致病性变异的病例。

结果

在100个不相关的先证者中鉴定了38个病原体。在这些变体中，在LDLR中鉴定出33个，在APOB中鉴定出3个，在PCSK9基因中鉴定出2个。十种致病变异是新颖的。根据改良的荷兰脂质临床网络标准，在被确定为确定的受试者中，有91.4％的受试者检测到突变，在可能的受试者中发现了40％，在可能的FH病例中检测到了18.8％。在北印度6个家庭中发现了LDLR基因的10号内含子（c.1587-1G> A）可能的创始人突变。在该队列中未检测到亚洲印第安人中APOB和PCSK9基因的常规致病变异以及以前在LDLR基因中报道的致病变异。

结论

这项研究证明了印度FH的遗传异质性。观察到的变异与西方人群中描述的变异不同。下一代测序技术有助于识别APOB基因中的新突变，这表明在研究较少的人群中，最好对整个基因进行测序而不是对特定突变进行测试。