Biotinidase Deficiency via the BTD Gene

Multiple carboxylase deficiency (MCD) is an inborn error of metabolism resulting from defective biotin metabolism. Juvenile-onset (also called late-onset) MCD (OMIM #253260) results from profound or partial deficiency of biotinidase, whereas early-onset MCD (OMIM #253270) is caused by holocarboxylase synthetase deficiency. Both forms of MCD are responsive to biotin therapy. 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 MCD 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 is documented. Untreated patients with partial biotinidase deficiency may experience fewer and milder symptoms than patients with complete deficiency (Suormala et al. J Inher Metab Dis 13:76-92, 1990). Asymptomatic adults with profound biotinidase deficiency have also been reported (Wolf et al. Am J Med Genet 73:5-9, 1997).

BTD-related multiple carboxylase deficiency (MCD) is an autosomal recessive disorder. Variants in the BTD gene (OMIM #609019) are the genetic cause of juvenile- or late-onset MCD. Over 100 BTD variants have been reported in children affected with profound biotinidase deficiency. Most pathogenic variants are missense variants, although nonsense, small insertions and deletions, and splice site variants have also been found. Three variants (p.Cys33Phefs*36, p.[Ala171Thr;Asp444His], and p.Gln456His) are commonly found in biotinidase-deficient newborns ascertained by newborn screening in the USA (Cowan et al. Genet Med 12:464-470, 2010). The p.Cys33Phefs*36 variant is found commonly in symptomatic patients (Norrgard et al. Pediatr Res 46:20-27, 1999). One other variant (p.Arg538Cys) is common among symptomatic children but not among newborns with a positive biotinidase screen (Pomponio et al. Hum Genet 99:506-512, 1997). The p.Asp444His variant reduces enzyme activity ~50% and results in a partial biotinidase deficiency when present in trans with a severe variant. The worldwide carrier frequency for BTD variants is thought to be 1 in 120 (Wolf et al. J Inherit Metab Dis 14:923-927, 1991).

Pomponio et al. (Pediat Res 42:840-848, 1997) identified variants on each BTD allele in all 30 biotinidase-deficient probands analyzed. The p.Arg538Cys and p.Cys33Phefs*36 variants accounted for over 50% of the mutant alleles in this study.

This test provides full coverage of all coding exons of the BTD 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).