Highlights
- •There is paucity of data on genetic studies of FH in Asian Indians.
- •100 unrelated cases with clinical suspicion of FH classified using modified DLCN.
- •Sanger sequencing of LDLR, PCSK9, 2 fragments of ApoB, and targeted lipid panel by NGS.
- •38 different disease-causing mutations (10 novel) identified in 47 unrelated cases.
- •Mutations identified in the study not reported before in Indians.
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.
Keywords
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Article info
Publication history
Published online: January 09, 2020
Accepted:
December 27,
2019
Received:
June 26,
2019
Footnotes
Conflict of interest: The authors state that there is no conflict of interest.
Identification
Copyright
© 2020 National Lipid Association. All rights reserved.
