Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency

Abstract

Holocarboxylase synthetase (HLCS) deficiency is a rare autosomal recessive disorder that presents with multiple life-threatening metabolic derangements including metabolic acidosis, ketosis, and hyperammonemia. A majority of HLCS deficiency patients respond to biotin therapy; however, some patients show only a partial or no response to biotin therapy. Here, we report a neonatal presentation of HLCS deficiency with partial response to biotin therapy. Sequencing of HLCS showed a novel heterozygous mutation in exon 5, c.996G>C (p.Gln332His), which likely abolishes the normal intron 6 splice donor site. Cytogenetic analysis revealed that the defect of the other allele is a paracentric inversion on chromosome 21 that disrupts HLCS. This case illustrates that in addition to facilitating necessary family testing, a molecular diagnosis can optimize management by providing a better explanation of the enzyme's underlying defect. It also emphasizes the potential benefit of a karyotype in cases in which molecular genetic testing fails to provide an explanation.

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

“…For example, Donti et al have revealed five cases of HLCS deficiency with broad differences in initial presentation and phenotype, and they have also described six novel pathogenic variants: c.500A > C (p.Tyr167Ser), c.1532A > T (p.Asn511Ile), c.2078G > C (p.Gly693Ala), c.977G > A (p.Gly326Glu), c.1710C > G (p.Asn570Lys), and c.1519 + 5G > A [9]. In addition, Quinonez et al have identified the novel heterozygous variant c.996G > C (p.Gln332His) and a paracentric inversion on chromosome 21 by utilizing cytogenetic analysis [10]. In this study, we investigated a Chinese Han pedigree with HLCS deficiency and described the relationship between molecular mutation and clinical manifestation.…”