Steatotic liver disease associated with 2,4-dienoyl-CoA reductase 1 deficiency

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered multifactorial with a number of predisposing gene polymorphisms known.

Methods: The occurrence of MASLD in 7 and 10 year old siblings, one without classical risk factors and one with type 2 diabetes suggested a monogenic etiology and prompted next-generation sequencing. Exome sequencing was performed in the proband, both parents and both siblings. The impact of a likely disease-causing DNA variant was assessed on the transcript and protein level.

Results: Two siblings have hepatomegaly, elevated serum transaminase activity, and steatosis and harbor a homozygous DECR1 splice-site variant, c.330+3A>T. The variant caused DECR1 transcript decay. Immunostaining demonstrated lack of DECR1 in patient liver.

Conclusions: These patients may represent the first individuals with DECR1 deficiency, then defining within MASLD an autosomal-recessive entity, well corresponding to the reported steatotic liver disease in Decr1 knockout mice. DECR1 may need to be considered in the genetic work-up of MASLD.

Fig. 1. DECR1 variant identification and transcript analysis.

A The patients’ parents (I-1, I-2) are cousins and heterozygous for the DECR1 variant c.330+3A>T B Their children II-2, II-3 have MASLD and are homozygous for this variant; the third (II-1) is homozygous for the wild-type (WT) allele. He has steatosis of the liver without fibrosis and without abnormality of serum biomarkers used to indicate hepatobiliary disease. C DECR1 c.330+3A>T variant leads to an aberrant transcript (left panel) that lacks intron 3 (right panel), which undergoes nonsense-mediated decay.

Fig. 2. Liver, Patient 1, with immunohistochemical controls (insets).

Macrovesicular steatosis A is manifest as vacuolation on staining with periodic acid–Schiff technique. Gömöri reticulin staining demonstrates mild portal-tract fibrosis and focal portal–portal bridging fibrosis B. Immunostaining for the antigens DECR1 and its homologue DECR2, with diaminobenzidine chromogen and haematoxylin counterstaining, identifies uniform lack of expression of DECR1 C and granular cytoplasmic expression of DECR2 D; same-slide control liver sections exhibit a granular marking pattern for both antigens. (Original magnifications 200x A, 100x B, and 400x C and D).