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Objective. In familial hypobetalipoproteinemia (FHBL), fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein (LDL) cholesterol, fatty liver and hepatocarcinoma displayed an autosomal dominant pattern of inheritance. Approach and Results. The proband was a 25 year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis and four more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in two participants with hypocholesterolemia and fatty liver. Approximately 22,400 single nucleotide variants were identi- ed in each sample. After variant ltering, 300 novel shared variants remained. A nonsense variant, p.K2240X due to an A>T mutation in exon 26 of APOB (c.6718A>T) was identi ed and this variant was con rmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show signi cant frequency differences between carriers and non-carriers of the c.6718A>T APOB gene mutation. Conclusions. We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.

Introduction. Primary hypobetalipoproteinemia (pHBL) is a monogenic heterogeneous condition inherited as a dominant or recessive trait characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) and/or apolipoprotein B (APOB) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL causing the familial hypobetalipoproteinemia (FHBL). Loss-of-function mutations in the PCSK9 gene also cause FHBL. Familial combined hypolipidemia is a recently discovered dyslipidemic phenotype characterized by low levels of TC, triglycerides (TG), LDL-C, and high-density lipoprotein cholesterol (HDL-C). The genetic cause of familial combined hypolipidemia has been attributed to mutations in the ANGPTL3 gene. methods and Results. In this report we describe a case of a young men with severe hypolipidemia characterized by low levels of total cholesterol, triglycerides and HDL- (54 mg/dl, 26 mg/dl, 17 mg/dl respectively). The proband’s mother and father showed normal plasma lipid values suggesting a recessive mode of inheritance of the phenotype. In order to identify the molecular defects the analysis of MTP and SARA2 genes was carried out and no mutations were identified in both genes. We extended our analysis to the other known genes responsible for pHBL and we were able to identify in the ANGPTL3 gene a novel splicing mutation (insT+3, IVS5) in homozigosity. Both parents were carriers of the same mutation in heterozygosity. InsT+3, IVS5 is predict to alter the correct splicing as predicted by in silico analysis. Conclusion. We describe a clinical case with severe hypolipidemia with a recessive mode of inheritance carrying a novel mutation in Intron 5 of ANGPTL3. The mode of inheritance and the clinical implications of familial combined hypolipidemia need to be further characterized.