Sultan Qaboos UniversityFahad AL Zadjali, PhD [email protected] 20/10/2017 1 DISCLOSURE OF CONFLICT No financial relationships with commercial interests 20/10/2017 2 CONSANGUINITY

Sultan QaboosUniversity

The genetics of familial hypercholesterolemia

making things simple

Fahad AL Zadjali, PhD

[email protected]/10/2017

1

DISCLOSURE OF CONFLICT

No financial relationships with commercial

interests

20/10/2017

2

CONSANGUINITY increases risk of monogenic disorders

• Monogenic Familial Hypercholosterolemia is most common monogenic disease

• FH is severely underdiagnosed with <1 % of the population. genetic cascade screening

Tadmouri GO et. al. Reprod Health. 2009

Familial Hypercholesterolemia

Polygenic Monogenic

Single or doubleHits/mutations

multipleHits/mutations

Polygenic LDL-C score

Lipoprotein metabolism

WHO / Fredrickson classification of primary hyperlipidaemias

Familial hypercholestrolemia

Type IIA Familial Hypercholesterolemia

Michael M Page, Aust Prescr 2016

LDLRAP1

Defects in LDLR• Autosomal dominant hypercholesterolemia

(ADH1) classical FH

• Attributes to 60-90% of FH cases.

• Loss of function mutations

>1700 variants

LDLR HomeUniversity College Londonwww.ucl.ac.uk/ldlr

Population Specific Mutations

Alallaf F. et. al. Open Cardiovasc Med J. 2017

LDLR mutations in Saudi Arabia

Oman LDLR mutations:

Novel

cDNA Protein

c.G1145T p.G382V

c.1214_1216del p.405_406del

c.1319_1332del p.R440fs

c.711delC p.R237fs

c.C1502T p.A501V

c.T1054C p.C352R

c.271delG p.G91fs

c.504_510del p.D168fs

c.G1171A p.A391T

c.G1027A p.G343S

c.G1285A p.V429M

c.G397A p.D133N

Apo B 100 gene defects

• Autosomal dominant hypercholesterolemia 2 (ADH 2) or Familial defective apoB100 (FDB)

• Attributes to about 5% of FH cases

• Loss of function mutations

Amanda J 2004, clinical Chemistry

29 exons

2/3 of mutations are in exon 26LDLR-binding domain

Amanda J 2004, clinical Chemistry

Proprotein convertasesubtilisin/kexin type 9 (PCSK9)

• Autosomal dominant hypercholesterolemia 3 (ADH 3)

• Gain of function mutations ( around 50)

• attributes to 1-3% of FH cases.

• Promotes degradation of LDLR

Mapping of common natural mutation of PCSK9 to the surface of the molecule.

Eric N. Hampton et al. PNAS 2007;104:14604-14609

©2007 by National Academy of Sciences

Autosomal Recessive Hypercholesterolemia (ARH)LDLRAP1

• Very rare

• Only patients with homozygous or compound heterozygous LDLRAP1 mutations are affected

Genetic testing for Familial Hypercholesterolemia

Next generation sequencing

EDTA-blood tubeSaliva sample

39.3

37.6

2.6

20.5

LDLR

ApoB

PCSK9

LDLRAP1

no mutation

Spectrum of mutations in SQUH

Double heterozygous mutation

Homozygous FH

2 normal LDLR

1 normal1 defective

LDLR

X

normal HeFH

1 normal1 defective

LDLR

X

HeFH

X

2 defective LDLR

X

HoFH

X

Large deletion / duplication of LDLR

Thoracic Key ®

Multiplex Ligation-dependent Probe amplification

Run on samples with negative mutations from NGS and no double hit mutations

Polygenic Hypercholesterolemia

• Individuals with elevated LDL-C similar to HeFH

• No Mutation detected in the 4 known genes, No deletion/duplication of LDLR.

• Identification is important as it will comprise the efficiency of cascade screening

Meta-analysis of plasma lipid concentrations in >100,000 individuals of European descent

12 SNPs genotype and quantify

LDL-C polygenic score

Teslovich TM et. al. Nature 2010

Futema M, Clin Chem 2015

Talmud PJ, The lancet 2013

ControlVs

FH- no mutation

ControlVs

FH with mutation

FH with mutationVsFH- no mutation

Diagnostic workflow for cascade testing in patients with familial hypercholesterolemia

Talmud PJ, The lancet 2013

A village of low HDL

Conclusion

• FH is caused by mutation of 4 genes LDLR, apoB100, PCSK9, LDLRAP1

• Next generation sequencing is cost effective to sequence the entire region of the 4 genes

• Identified mutations apply cascade screening

for 1st degree relatives

• Non-identified mutations polygenic LDL-C score