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Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH:  LDLR ,  APOB ,  PCSK9  and  APOE . Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the  LDLR ,  PCSK9  and  APOE  genes and fragments of exons 26 and 29 of  APOB  gene. We identified in one family a p.Arg50Gln mutation in the  APOB  gene, which occurs in a region not usually associated with ADH. Segregation and  in-silico  analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of  APOB , one patient with a severe phenotype carrying also a mutation in  PCSK9 : p.Arg96Cys. This is the first compound heterozygote reported with a mutation in  APOB  and  PCSK9 . Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.

New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia