Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome

Am J Med Genet A. 2018 Feb;176(2):351-358. doi: 10.1002/ajmg.a.38578. Epub 2017 Dec 19.


22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.

Keywords: 22q11.2 deletion syndrome; SLC25A1; agenesis of the corpus callosum.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Agenesis of Corpus Callosum / diagnostic imaging
  • Agenesis of Corpus Callosum / genetics
  • Alleles
  • Anion Transport Proteins / chemistry
  • Anion Transport Proteins / genetics
  • Base Sequence
  • Brain Diseases, Metabolic, Inborn / diagnosis*
  • Brain Diseases, Metabolic, Inborn / genetics*
  • DiGeorge Syndrome / diagnosis*
  • DiGeorge Syndrome / genetics*
  • Female
  • Genes, Recessive*
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics
  • Mutation
  • Organic Anion Transporters
  • Sequence Analysis, DNA


  • Anion Transport Proteins
  • Mitochondrial Proteins
  • Organic Anion Transporters
  • Slc25a1 protein, human

Supplementary concepts

  • 2-Hydroxyglutaricaciduria