Clinical relevance of short-chain acyl-CoA dehydrogenase (SCAD) deficiency: Exploring the role of new variants including the first SCAD-disease-causing allele carrying a synonymous mutation
Tonin, R.; Caciotti, A.; Funghini, S.; Pasquini, E.; Mooney, S.D.; Cai, B.; Proncopio, E.; Donati, M.A.; Baronio, F.; Bettocchi, I.; Cassio, A.; Biasucci, G.; Bordugo, A.; la Marca, G.; Guerrini, R.; Morrone, A.
Bba Clinical 5: 114-119
ISSN/ISBN: 2214-6474 PMID: 27051597 DOI: 10.1016/j.bbacli.2016.03.004
Short-chain acyl-coA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation caused by ACADS gene alterations. SCADD is a heterogeneous condition, sometimes considered to be solely a biochemical condition given that it has been associated with variable clinical phenotypes ranging from no symptoms or signs to metabolic decompensation occurring early in life. A reason for this variability is due to SCAD alterations, such as the common p.Gly209Ser, that confer a disease susceptibility state but require a complex multifactorial/polygenic condition to manifest clinically. Our study focuses on 12 SCADD patients carrying 11 new ACADS variants, with the purpose of defining genotype-phenotype correlations based on clinical data, metabolite evaluation, molecular analyses, and in silico functional analyses. Interestingly, we identified a synonymous variant, c.765G > T (p.Gly255Gly) that influences ACADS mRNA splicing accuracy. mRNA characterisation demonstrated that this variant leads to an aberrant splicing product, harbouring a premature stop codon. Molecular analysis and in silico tools are able to characterise ACADS variants, identifying the severe mutations and consequently indicating which patients could benefit from a long term follow- up. We also emphasise that synonymous mutations can be relevant features and potentially associated with SCADD.