Clinical, biochemical, and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

BMC Med Genet. 2020 Jul 29;21(1):155. doi: 10.1186/s12881-020-01080-4.


Background: Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in defects in several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions.

Case presentation: In this paper, we report a Chinese Han pedigree with HLCS deficiency diagnosed by using next-generation sequencing and validated with Sanger sequencing of the HLCS and BTD genes. The Chinese proband carries the common missense mutation c.1522C > T (p.Arg508Trp) in exon 9 of the HLCS gene, which generates an increased Km value for biotin. A novel frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15) in exon 6 of the HLCS gene is predicted to be deleterious through PROVEAN and MutationTaster. A novel heterozygous mutation, c.638_642delAACAC (p.His213Profs*4), in the BTD gene is also identified.

Conclusions: The Chinese proband carries the reported Arg508Trp variant, the novel 2-bp frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15), which expands the mutational spectrum of the HLCS gene, and the novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4), which expands the mutational spectrum of the BTD gene. Furthermore, reversible hearing damage is rarely reported in patients with HLCS deficiency, which deserves further discussion.

Keywords: Arg508Trp; Case report; Frameshift mutation; HLCS deficiency; Hearing damage.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Asian People / genetics*
  • Base Sequence
  • Carbon-Nitrogen Ligases / chemistry
  • Carbon-Nitrogen Ligases / genetics
  • Ethnicity / genetics*
  • Female
  • Holocarboxylase Synthetase Deficiency / blood
  • Holocarboxylase Synthetase Deficiency / enzymology
  • Holocarboxylase Synthetase Deficiency / genetics*
  • Holocarboxylase Synthetase Deficiency / urine
  • Humans
  • Infant
  • Male
  • Metabolome
  • Mutation / genetics
  • Pedigree*
  • Protein Domains


  • Carbon-Nitrogen Ligases
  • holocarboxylase synthetases