Spectrum of mutations in homozygous familial hypercholesterolemia in India, with four novel mutations.
Homozygous familial hypercholesterolemia (FH) is a rare but serious, inherited disorder of lipid metabolism characterized by very high total and LDL cholesterol levels from birth. It presents as cutaneous and tendon xanthomas since childhood, with or without cardiac involvement. FH is commonly caused by mutations in three genes, i.e. LDL receptor (LDLR), apolipoprotein B (ApoB) and PCSK9. We aimed to determine the spectrum of mutations in cases of homozygous FH in Asian Indians and evaluate if there was any similarity to the mutations observed in Caucasians.



Sixteen homozygous FH subjects from eleven families were analyzed for mutations by Sanger sequencing. Large rearrangements in LDLR gene were evaluated by multiplex ligation probe dependent amplification (MLPA) technique.



Ten mutations were observed in LDLR gene, of which four mutations were novel. No mutation was detected in ApoB gene and common PCSK9 mutation (p.D374Y). Fourteen cases had homozygous mutations; one had compound heterozygous mutation, while no mutation was detected in one clinically homozygous case. We report an interesting "Triple hit" case with features of homozygous FH.



The spectrum of mutations in the Asian Indian population is quite heterogeneous. Of the mutations identified, 40% were novel. No mutation was observed in exons 3, 9 and 14 of LDLR gene, which are considered to be hot spots in studies done on Asian Indians in South Africa. Early detection followed by aggressive therapy, and cascade screening of extended families has been initiated to reduce the morbidity and mortality in these patients.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, 110060, India. Electronic address: nitikasetia@gmail.com.
Nitika
N
Setia
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, 110060, India.
Renu
R
Saxena
Hyperlipidemia Prevention Clinic, Department of Cardiology, Sir Ganga Ram Hospital, New Delhi, 110060, India.
Anjali
A
Arora
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, 110060, India.
Ishwar C
IC
Verma
D000293:Adolescent; D000328:Adult; D053299:Apolipoprotein B-100 / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D007194:India / Q000453:epidemiology; D007223:Infant; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics; D055815:Young Adult
C569471:APOB protein, human; D053299:Apolipoprotein B-100; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
Homozygous FH; Mutation screening; New mutations