title: 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.
authors: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Shane C
authors: SC
authors: Quinonez
authors: Department of Pediatrics, Geisinger Medical Center, Danville, PA, USA.
authors: Andrea H
authors: AH
authors: Seeley
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Cindy
authors: C
authors: Lam
authors: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Thomas W
authors: TW
authors: Glover
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
authors: Bruce A
authors: BA
authors: Barshop
authors: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA. keeganc@med.umich.edu.|Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA. keeganc@med.umich.edu.|Division of Genetics, Department of Pediatrics, University of Michigan Medical School, 3520 MSRBI, SPC 5652, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA. keeganc@med.umich.edu.
authors: Catherine E
authors: CE
authors: Keegan
keywords: Biotin; Cytogenetics; Genotype–phenotype correlation; Holocarboxylase synthetase deficiency; Inborn error of metabolism; Lactic acidosis