1. Spectrum of genetic variants associated with Familial Hypercholesterolemia and phenotype / genotype relationship in cases of our population
Universidad de
Buenos Aires
Virginia G Bañares1, Pablo Corral2, Silvina Quintana3, Graciela Lopez4, Maria Beatriz Araujo5, Gabriela Berg4, Laura Schreier4
1- Centro Nacional de Genética Médica, ANLIS; 2- Facultad de Medicina, Universidad FASTA, Mar del Plata, Buenos Aires; 3- Instituto Fares Taie, Mar del Plata, Buenos Aires; 4- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, INFIBIOC-UBA; 5- Servicio de Nutrición, Hospital Nacional de Pediatría ¨Dr. Juan P Garraham¨.
Introduction
Familial hypercholesterolemia (FH) is caracterizad by: high level LDL-c and elevated premature coronary heart disease (CHD) risk.
The score of the Dutch Lipid Clinic Network (DLCN) allows their clinical identification: 6-8 points means ¨probable¨ and >8 ¨definitive¨.
Is caused by mutations in genes: LDLR, APOB and PCSK9, or others like APOE or LDLRAP1 in the recessive form. More than 3000 genetics variants reported. ≈90% on LDLR gene, ≈8% APOB and ≈1% PCSK9. Not founder effects.
An early identification is crucial because of the cumulative effect of LDL- c on the arteries but FH unambiguous clinical/biochemical identification in young people is not easy.
The early identification can be doing detecting carriers of genetic variants previously identifies in the index case of a family.
Results
47% of IC were carriers of variants. When relatives were included the detection rate reaches 54%.
29% of variants were null allele type.
25% VUS, figure 3.
8 variants observed in more than one IC: LDLR c.2043C>A 11.2%(6).
40 different variants, the distribution between genes is shown in figure 1.
Exons with most mutations; LDLR 14, 7 and 4, which represents 23% of the IC.
9% indels and 4% large rearregments figure 2.
Figure 3: type of variant identified.
VUS – variant uncertain significance, LP like pathogenic, P pathogenic
Figure 1: Distribution of variants between genes.
Figure 2: Distribution of variants between genes.
correlation phenotype / genotype
52.9% phenotype +/genotype +
39.7% phenotype +/genotype –
1.5% phenotype -/genotype + *
* 2 cases detected in the family cascade study.
The most common DLCN value was 7(17%) with 42% of variants; for DLCN values ≥8, 60% or more presented variants; while DLCN of %, figure 4.
Objectives
Here we present an update of the spectrum mutations in our population and a family with a non-conventional phenotype/genotype relationship. 
LDLR c.1846-?_2311+?del
Sample & Methods
100 index cases (IC): 87 adults and 13 children; 8 were severe forms.
Identifies variants were traced in 36 relatives
NGS panel: LDLR, APOB, PCSK9, LDLRAP1 and APOE (Refseq, Hg19, NM_ , NM_ , NM_ , NM_ and NM_ ).
The variants were classified according to the ACMG 2015 criteria in: pathogenic (P), Like pathogenic (LP) or of uncertain significance (VUS).
Novel variants were considered those not listed in the LOVD, HMDB and ClinVar databases.
LDLR c.1895A>T
PCSK9 c delC
LDLR c.1895A>T ;
c.1846-?_2311+?del
LDLR c.1846-?_2311+?del
Figure 4: Distribution of genetic variants between DLCN values
Clinically FH homocigous FH heterocigous
Conclusions
FH presents great heterogeneity in our population. The most common variant, c.2043C>A, was found in 11% of the IC. 25% of the variants lack functional studies and have an uncertain significance.
The family cascade study favors the identification of carriers that increase the cost-benefit ratio of the genetic study, it is necessary to identify variants that can modulate the phenotypic expression and still apply little in our population.