Inherited non-alcoholic fatty liver disease and dyslipidemia due to monoallelic ABHD5 mutations

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition and the most common liver disease worldwide, affecting more than one-third of the population. So far there have been no reports on mendelian inheritance in families with NAFLD. Methods: We performed whole-exome or targeted next-generation sequencing on patients with autosomal dominant NAFLD. Results: We report a heritable form of NAFLD and/or dyslipidemia due to monoallelic ABHD5 mutations, with complete clinical expression after the fourth decade of life, in 7 unrelated multiplex families encompassing 39 affected individuals. The prevalence of ABHD5-associated NAFLD was estimated to be 1 in 1,137 individuals in a normal population. Conclusion: We associate a Mendelian form of NAFLD and/or dyslipidemia with monoallelic ABHD5 mutations. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a common multifactorial disorder with a strong genetic component. Inherited forms of NAFLD have been suspected but, their molecular pathogenesis has not been disclosed. Here we report a heritable form of NAFLD with clinical expression after 40 years of age, associated with monoallelic ABHD5 mutations. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.