Genotype-phenotype correlation of 33 patients with maple syrup urine disease

Am J Med Genet A. 2020 Nov;182(11):2486-2500. doi: 10.1002/ajmg.a.61806. Epub 2020 Aug 19.


Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder due to defects in the branched-chain α-ketoacid dehydrogenase complex (BCKDC). MSUD varies in severity and its clinical spectrum is quite broad, ranging from mild to severe phenotypes. Thirty-three MSUD patients were recruited into this study for molecular genetic variant profiling and genotype-phenotype correlation. Except for one patient, all other patients presented with the classic neonatal form of the disease. Seventeen different variants were detected where nine were novel. The detected variants spanned across the entire BCKDHA, BCKDHB and DBT genes. All variants were in homozygous forms. The commonest alterations were nonsense and frameshift variants, followed by missense variants. For the prediction of variant's pathogenicity, we used molecular modeling and several in silico tools including SIFT, Polyphen2, Condel, and Provean. In addition, six other tools were used for the prediction of the conservation of the variants' sites including Eigen-PC, GERP++, SiPhy, PhastCons vertebrates and primates, and PhyloP100 rank scores. Herein, we presented a comprehensive characterization of a large cohort of patients with MSUD. The clinical severity of the variants' phenotypes was well correlated with the genotypes. The study underscores the importance of the use of in silico analysis of MSUD genotypes for the prediction of the clinical outcomes in patients with MSUD.

Keywords: genotype-phenotype correlation; in silico tools; maple syrup urine disease; variants of BCKDH complex.

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • DNA Mutational Analysis*
  • Female
  • Frameshift Mutation
  • Genetic Association Studies*
  • Homozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Isoleucine / genetics
  • Leucine / genetics
  • Male
  • Maple Syrup Urine Disease / diagnosis*
  • Maple Syrup Urine Disease / genetics*
  • Maple Syrup Urine Disease / therapy
  • Molecular Biology
  • Mutation, Missense
  • Patient Readmission
  • Phenotype
  • Pyruvate Decarboxylase / genetics*
  • Tandem Mass Spectrometry


  • Isoleucine
  • Pyruvate Decarboxylase
  • Leucine