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Research Project
Clinical and molecular study of familial lipoprotein disorders with increase cardiovascular risk
Funder
Authors
Publications
Looks Like FH But it’s not FH: Extended Lipid Profile of Paediatric Clinical FH Patients Reveals a Different Lipid Profile in FH Negative Patients
Publication . Medeiros, A.M.; Aguiar, P.; Bourbon, Mafalda
Aim: Familial
Hypercholesterolemia
(FH)
is
a
common
autosomal
dominant
disorder,
caused
by
mutations
in
genes
involved
in
cholesterol’s
clearance
(LDLR,
APOB,
PCSK
9).
Clinical
diagnosis
is
usually
based
on
high
total
cholesterol
or
LDL-C
levels
and
family
history
of
premature
coronary
heart
disease.
Using
an
extended
lipid
profile
of
paediatric
dyslipidemic
patients,
we
aim
to
identify
biomarkers
for
a
better
diagnosis
of
FH
in
clinical
settings.
Genetic Screening of Familial Hypercholesterolemia in Portugal
Publication . Medeiros, A.M.; Alves, A.C.; Bourbon, Mafalda
Purpose: Familial hypercholesterolemia (FH) is a common autosomal dominant
disorder of lipid metabolism (1:500 frequency), caused by mutations in
LDLR, APOB, PCSK9 genes. FH patients have high levels of plasma
cholesterol since birth, accelerated atherosclerosis and, without
treatment, increased risk of premature coronary heart disease (pCHD).
WHO recommends universal screening of FH, since there is a
definite/genetic diagnosis and pharmacological treatment that reduces
patients’ cardiovascular risk. Portugal doesn’t have a national screening
programme for FH but, in 1999, it was established the Portuguese FH
Study (PFHS) that aims to determine prevalence/distribution of FH in
Portugal in order to promote the early identification and characterization
of FH patients and improve their prognosis.
Mutational Analysis of the Portuguese Cohort with Clinical Diagnosis of Familial Hypercholesterolemia
Publication . Medeiros, A.M.; Alves, A.C.; Bourbon, Mafalda
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder of lipid metabolism (1:500). FH patients present high levels of plasma cholesterol since birth, and if untreated, develop premature coronary heart disease (pCHD). To fulfil the World Health Organization recommendation (1998 report), the Portuguese FH Study was established in 1999. The aim of the Portuguese FH Study is to promote early identification and characterization of FH patients in order to decrease their cardiovascular risk by the implementation of correct/adequate and early counselling/treatment.
Using percentiles to diagnose familial hypercholesterolemia in Portugal
Publication . Pereira, A.; Alves, A.C.; Medeiros, A.M.; Mariano, Cibelle; Bourbon, Mafalda
Aims: Familial
hypercholesterolemia
(FH)
is
a
genetic
disorder
of
lipid
metabolism,
clinically
characterised
by
high
levels
of
low-density
lipoprotein
cholesterol
(LDL-C)
that
leads
to
cholesterol
accumulation
in
tendons
and
arteries,
premature
atherosclerosis
and
increased
risk
of
premature
coronary
heart
disease.
In
1999,
the
Portuguese
FH
Study
was
established
at
the
National
Institute
of
Health
to
identify
the
genetic
cause
of
hypercholesterolemia
in
individuals
with
a
clinical
diagnosis
of
FH
and
to
perform
an
epidemiologic
study
to
determine
the
prevalence
and
distribution
of
FH
in
Portugal.
In
the
last
16
years,
a
genetic
defect
was
identified
in
749
patients,
representing
3.
7
%
of
the
cases
estimated
to
exist
in
Portugal.
Index
patients
were
included
in
this
study
using
the
Simon
Broome
(SB)
criteria.
However,
there
are
different
FH
clinical
criteria
to
diagnose
index
cases.
Since
there
are
no
clinical
criteria
to
identify
relatives
with
FH,
the
aim
of
this
work
was
to
investigate
if
a
diagnostic
tool
based
on
population
specific
95
th
percentile
improves
the
clinical
identification
of
Portuguese
FH
patients
comparing
with
SB
criteria.
Genetic background of individuals with clinical diagnosis of FH from the Portuguese FH Study cohort
Publication . Medeiros, Ana Margarida; Alves, Ana Catarina; Chora, Joana Rita; Miranda, Beatriz Raposo; Bourbon, Mafalda
Aim: Familial Hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism associated to increased CAD risk. Three genes are associated with FH (LDLR, APOB, PCSK9). Variants in FH phenocopies genes (LDLRAP1, APOE, LIPA, ABCG5, ABCG8), LDL-C polygenic risk score (PRS) and hyper-Lp(a) can mimic the FH phenotype. In the present work we intend to unravel the genetic background in individuals with clinical diagnosis of FH.
Methods: A biochemical and genetic study was performed to 1005 patients with clinical diagnosis of FH referred to the Portuguese FH Study until December 2021. Since 2017, genetic diagnosis is performed by an NGS panel with 8 genes and 6-SNPs to determine PRS.
Results: FH was genetically confirmed in 41% of the cases. In the FH-negative cohort (N=590), 30% (N=177) present Lp(a)>50mg/dl, 16% (N=95) have high PRS, 1% (N=7) have other monogenic cause and 1% (N=7) have one pathogenic variant in ABCG5/ABCG8. Additionally, 11% (N=61) carry heterozygous VUS in either LDLR, APOB or PCSK9 and 5% (N=29) carry heterozygous variants of unknown significance (VUS) in FH phenocopies genes. No identifiable cause of dyslipidemia was found in the remaining 36% patients.
Conclusions: Overall, FH was confirmed genetically in 41% of the cohort. In 50% of the FH negatives the FH phenotype can be caused by Hyper-Lp(a) or high PRS. A small part of patients has pathogenic variants in ABCG5/8 in heterozygosity and this can be the cause of hypercholesterolemia and should be further investigated. This extended NGS panel is important to identify FH/FH-phenocopies and therefore personalize each patient’s treatment
Organizational Units
Description
Keywords
Contributors
Funders
Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
5646-ICCMS
Funding Award Number
PIC/IC/83333/2007