Homozygous mutation in the ADH6 gene, involved in alcohol metabolism, associated with a multisystem disorder, analogous to the fetal alcohol syndrome

Abstract

Introduction: In humans, there is considerable individual variability in ethanol metabolism, and these differences have been partially attributed to genetic variability at the ADH locus at 4q22-23, where seven genes are found. They encode ADH enzymes with different kinetic and structural properties that represent the first step in a series of reactions involved in the metabolism and elimination of alcohol from the body. The objective of the study was to identify the potential genetic cause in a patient with congenital metabolic encephalopathy of unknown etiology, and having similarities to fetal alcohol syndrome. Case: We described a patient of Moroccan origin who suffered from a multisystem disorder compatible with congenital metabolic encephalopathy. The main clinical characteristics observed in the patient were psychomotor retardation, facial dysmorphism, microcephaly, and hematologic and endocrine abnormalities. Whole exome sequencing identified a homozygous missense mutation c.133G > A (p.Gly45Arg) in ADH6, a gene implicated in alcohol metabolism and previously not associated with human disease. The variant segregates well with the disease in the family, affects a highly conserved amino acid and was predicted to be damaging. Bioinformatics analysis revealed that the Gly45Arg substitution may affect the structure and function of the ADH6 protein. No other potential causal gene under an autosomal recessive inheritance model was found. Discussion: The patient presented with a congenital metabolic encephalopathy, and having similarities to fetal alcohol syndrome due to prenatal alcohol exposure. The only potential causing variant was identified in the ADH6, belonging to the Class V ADH which is a predominantly fetal alcohol dehydrogenase. In addition, he presented vacuolated lymphocytes, anemia and abnormalities of endocrine function, all have been reported to be related to an abnormal alcohol metabolism. Conclusion: We identified a novel variant in ADH6, involved in the metabolism of alcohol, in a patient with a hereditary alcohol metabolism encephalopathy syndrome.

Keywords

• Whole exome sequencing
• Novel mutation
• ADH6
• Alcohol metabolism
• Genetic disorder