Holocarboxylase Synthetase Deficiency via the HLCS Gene

Multiple carboxylase deficiency (MCD) is an inborn error of metabolism resulting from defective biotin metabolism. Early-onset MCD (OMIM #253270) results from deficiency of holocarboxylase synthetase (HLCS), whereas juvenile (also called late)-onset MCD (OMIM #253260) is caused by biotinidase (BTD) deficiency. BTD and HLCS forms of MCD are both responsive to biotin therapy. However, making a distinction between the two types is difficult and relies largely on age of onset rather than clinical features. Clinical signs of juvenile-onset BTD typically appear after 3 months of age while early-onset MCD is typically evident earlier than 3 months of age (Wolf et al. Ann Neurol 18:614-617, 1985). In vitro enzyme studies are capable of distinguishing between the two disorders. The earliest presenting sign is usually seizures, but other early, non-specific symptoms include hypotonia, respiratory symptoms, developmental delay, and ataxia. Eczema, alopecia, dermatitis, and skin infections are also common findings, and cutaneous presentations in conjunction with neurological symptoms greatly limit the differential diagnosis. Clinical variability for HLCS-related MCD is documented, and an asymptomatic homozygous adult has been reported (Suzuki et al. Hum Mutat 26:285-290, 2005).

HLCS-related multiple carboxylase deficiency (MCD) is an autosomal recessive disorder. Variants in the HLCS gene are the genetic cause of early-onset MCD. Approximately 30 HLCS variants have been reported. Most variants are missense changes but nonsense variants, small insertions and deletions, gross deletions, and splice site variants have also been found. Among Northern Europeans a splice site variant (c.1519+5G>A) is prevalent, and among Japanese patients two variants (p.Leu237Pro and p.Gly261Valfs*20) are predominant (Suzuki et al. Hum Mutat 26:285-290, 2005). The p.Arg508Trp variant has been found in multiple patients from several ethnic groups in East Asia, the Middle East, and the USA (Suzuki et al. Hum Mutat 26:285-290, 2005).

Dupuis et al. (Hum Molec Genet 5:1011-1016, 1996) found two causative HLCS variants in each of nine patients studied, and Aoki et al. (Hum Genet 104:143-148, 1999) found two causative variants in each of their seven holocarboxylase synthetase deficient patients.

This test provides full coverage of all coding exons of the HLCS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).