Endocrine Abstracts

Background and aims: To assess the prevalence and variability of pathogenic or likely pathogenic autosomal dominant mutations (ADM) of Familial Hypercholesterolemia (FH) in a Finnish cohort of patients with premature coronary artery disease (CAD) and elevated LDL-C levels.

Methods: Study population was enrolled from 162 patients diagnosed with premature CAD (men < 55 years and women < 60 years) and history of high LDL-C (≥ 5 mmol/l) levels, without apparent secondary reason for hypercholesterolemia, treated in the Heart Hospital at Tampere University Hospital between 2007 and 2017. A total of 80 patients were available for genetic testing for FH, 21 patients were studied during standard treatment and 59 patients were recruited for genetic testing retrospectively. Clinical probability of FH was assessed using the Dutch Lipid Clinic Network (DLCN) – Criteria: possible (DLCNC = 5), probable (DLCNC 6-8), definite (DLCNC ≥ 9). All patients were studied for Finnish LDLR gene founder mutations (FH-Helsinki (9,5 kb deletion including exons 1–18), FH-North-Karelia (c.925_931delCCCATCA, p.(Pro309Lysfs*59)), FH-Pori (c.1202T>A, p.(Leu401His)), FH-Turku (c.2531G>A, p.(Gly844Asp)). Further testing of the genes LDLR (Sanger sequencing and MLPA), PCSK9 (Sanger sequencing) and APOB (Sanger sequencing for mutations affecting codon 3527 in exon 26) was conducted to 62 (78%) patients if a founder mutation was not discovered.

Results: Out of 80 patients four (5%) had definite FH, 54 (68%) had probable FH and 22 (27%) had possible FH based on DLCN - criteria. Pathogenic ADM of FH was found in five patients (6%). Four founder mutations and one additional LDLR- mutation were discovered. Based on clinical criteria three patients had definite FH and two patients had probable FH. ADM’s of FH weren’t discovered in 91% (53/58) of patients with probable/definite FH and in none of the patients with possible FH.

Conclusions: Despite possible selection bias, proportion of patients with ADM’s of FH was lower than expected in a population with elevated LDL-C levels, premature CAD and clinical phenotype of FH. Only a minority of patients with clinically defined FH, studied for genetic mutations, had monogenic FH. Further studies in our area are required to identify the population where genetic testing of FH is likely to offer the greatest clinical advantages.