title: 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.
abstract: 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.
authors.affiliation: Clin Paed Neurol & Lab, Meyer Child Hosp, Florence, Italy; Dept of Neurofarba, Univ of Florence, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Tonin
authors.affiliation: Clin Paed Neurol & Lab, Meyer Child Hosp, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.affiliation: Newborn Screen Biochem & Pharm Lab, Meyer Child Hosp, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Funghini
authors.affiliation: Metabolic Unit, A. Meyer Children's Hospital, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pasquini
authors.affiliation: University of Washington, Biomedical and Health Informatics, Seattle, WA, USA.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.affiliation: University of Washington, Biomedical and Health Informatics, Seattle, WA, USA.
authors.forename: Binghuang
authors.initials: B
authors.lastname: Cai
authors.affiliation: Metabolic Unit, A. Meyer Children's Hospital, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Proncopio
authors.affiliation: Metabolic Unit, A. Meyer Children's Hospital, Florence, Italy.
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.affiliation: Dept of Paed, Univ of Bologna, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Baronio
authors.affiliation: Dept of Paed, Univ of Bologna, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bettocchi
authors.affiliation: Dept of Paed, Univ of Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cassio
authors.affiliation: Dept of Paed and Neonatology, Piacenza Hosp, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Biasucci
authors.affiliation: Dept of Paed and Inher Met Dis Unit, AOUI Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bordugo
authors.affiliation: Newborn Screen Biochem & Pharm Lab, Meyer Child Hosp, Florence, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.affiliation: Clin Paed Neurol & Lab, Meyer Child Hosp, Florence, Italy; Dept of Neurofarba, Univ of Florence, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Clin Paed Neurol & Lab, Meyer Child Hosp, Florence, Italy; Dept of Neurofarba, Univ of Florence, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
keywords: ACADS; ACADS, Acyl CoA-deydrogenase, short chain; C4-C, butyrylcarnitine; EMA, ethylmalonic acid; LC–MS/MS, Tandem mass spectrometry; NBS, Newborn screening; SCAD; SCAD, Short-chain acyl-CoA dehydrogenase; SCADD, Short-chain acyl-CoA dehydrogenase deficiency; Short-chain acyl-CoA dehydrogenase; Synonymous mutation