Aims
Mutations in the LDLR, APOB and PCSK9 genes affecting the LDL-receptor pathway are known to cause autosomal dominant Familial Hypercholesterolaemia (FH). In approximately 20% of probands with a definite clinical diagnosis of FH no mutations are detected suggesting that there are FH causing mutations located in other genes. However it is proposed that polygenic SNP scores above the median in mutation negative patients infer a low likelihood of monogenic FH. 
Methods
We compared the frequency of pathogenic mutations among FH probands in relation to deciles of polygenic SNP scores. DNA samples from probands were tested using a bespoke MALDI-TOF Sequenom mass spectrometry assay incorporating the 12 SNP LDL score followed by Next Generation Sequencing (NGS, MiSeq/Multiplicom). 

Results
Of the 478 FH probands tested, 125 had a polygenic SNP score below the median, of which 42 % were mutation positive. 353 probands had a polygenic SNP score above the median, of which 19% were mutation positive. We also found that 41% of mutation positive FH patients have polygenic SNP scores in the top 3 deciles. Four unrelated probands with the pathogenic APOE mutation (APOE
c.500_502delTCC p.(Leu167del) had polygenic SNP scores that would be considered compatible with polygenic hypercholesterolaemia (5th-10th decile).

Conclusions
Polygenic SNP scores have low sensitivity for monogenic causes of FH and could lead to misclassification of patients. Patients with monogenic FH frequently have high polygenic SNP scores. Patients with autosomal dominant mutations in the APOE gene may be missed entirely if they are classified as polygenic hypercholesterolaemia.

06 - HIGH POLYGENIC SNP SCORES DO NOT EXCLUDE MONOGENIC FAMILIAL HYPERCHOLESTEROLAEMIA