Objective. In familial hypobetalipoproteinemia (FHBL), fatty liveris a characteristic feature, and there are several reports of associatedcirrhosis and hepatocarcinoma. We investigated a large kindredin which low-density lipoprotein (LDL) cholesterol, fatty liverand hepatocarcinoma displayed an autosomal dominant pattern ofinheritance.Approach and Results. The proband was a 25 year-old female withlow plasma cholesterol and hepatic steatosis. Low plasma levels oftotal cholesterol and fatty liver were observed in 10 more familymembers; 1 member was affected by liver cirrhosis and four moresubjects died of either hepatocarcinoma or carcinoma on cirrhosis.To identify the causal mutation in this family, we performed exomesequencing in two participants with hypocholesterolemia and fattyliver. Approximately 22,400 single nucleotide variants were identi- ed in each sample. After variant ltering, 300 novel shared variantsremained. A nonsense variant, p.K2240X due to an A>T mutationin exon 26 of APOB (c.6718A>T) was identi ed and this variantwas con rmed by Sanger sequencing. The gentotypic analysis of16 family members in total showed that this mutation segregatedwith the low cholesterol trait. In addition, genotyping of the PNPLA3p.I148M did not show signi cant frequency differences between carriersand non-carriers of the c.6718A>T APOB gene mutation.Conclusions. We used exome sequencing to discover a novelnonsense mutation in exon 26 of APOB (p.K2240X) responsiblefor low cholesterol and fatty liver in a large kindred.This mutation may also be responsible for cirrhosis and liver cancerin this family.
Lingua originaleEnglish
Numero di pagine1
Stato di pubblicazionePublished - 2013


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