Search

Background & aimsLean patients with non-alcoholic fatty liver disease (NAFLD) represent 10-20% of the affected population and may have heterogeneous drivers of disease. We have recently proposed the evaluation of patients with lean NAFLD without visceral adiposity for rare monogenic drivers of disease. Here, we aimed to validate this framework in a well-characterised cohort of patients with biopsy-proven NAFLD by performing whole exome sequencing.MethodsThis prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness.ResultsSix patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in ALDOB (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B (APOB). The pathogenicity of this APOB variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta = -0.51 g/L, 95% CI -0.65 to -0.36 g/L, p = 1.4 × 10-11) and higher liver fat on MRI (beta = +10.4%, 95% CI 4.3-16.5%, p = 8.8 × 10-4). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia.ConclusionsIn this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype.Impact and implicationsAlthough most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease.

Whereas the rising prevalence of nonalcoholic fatty liver disease (NAFLD) is closely related with the global obesity epidemic, up to 10–20% of individuals with NAFLD are lean as defined by a body mass index of < 25 kg/m2, or < 23 kg/m2 in Asians. This entity designated as “lean NAFLD” is estimated to affect 8 to 10 million individuals in the United States alone. Here, we review the emerging data on the epidemiology, natural history and prognosis of lean NAFLD and put forward a diagnostic approach that combines detailed clinical phenotyping with genomic analysis. We propose two subtypes of lean NAFLD referred to as type 1: individuals with visceral adiposity and insulin resistance but normal BMI; and type 2: lean individuals with hepatic steatosis secondary to a known or unknown monogenic disease. We envision that incorporation of genomic analysis in the diagnostic algorithm of lean patients with NAFLD will elucidate the contribution of common genetic variants through the calculation of NAFLD polygenic risk score and also characterize the diverse array of rare monogenic diseases that can lead to triglyceride accumulation in the cytoplasm of hepatocytes. Collectively, the integration of a molecular diagnosis in the clinical evaluation of patients with lean NAFLD will provide an accurate diagnosis, with possible targeted therapies and may uncover novel molecular mechanisms with potential broader therapeutic implications.

Mitochondrial diseases (MD) are a group of rare inherited disorders, characterized by phenotypic heterogeneity, with hitherto no effective therapeutic options. The aim of this study was to develop a next generation sequencing (NGS) strategy, by using a custom gene panel and whole mitochondrial genome, to identify the disease causing pathogenic variants in 146 patients suspicious of MD. The molecular analysis of this cohort revealed six novel and 15 described pathogenic variants, as well as 26 variants of unknown significance. Our findings are expanding the mutational landscape of these disorders and support the use of a NGS strategy for a higher diagnostic yield. • NGS strategy for mitochondrial diseases diagnosis, with a good balance between cost, time and amount of data for analysis. • Study of genes with a very reduced number of mutations reported. • Identification of novel mutations in nuclear genes associated with mitochondrial diseases. • Evaluation of the first Portuguese patient's cohort suspected of mitochondrial dysfunction investigated by targeted NGS. [ABSTRACT FROM AUTHOR]