rs398123138 — BTD

Pathogenic 5-bp frameshift deletion in the biotinidase enzyme gene, eliminating the final 41 amino acids of the protein and causing biotinidase deficiency when inherited in biallelic form; heterozygotes are asymptomatic carriers

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BTD c.1448_1452del — Frameshift Deletion Causing Biotinidase Deficiency

Biotinidase11 Biotinidase
Encoded by the BTD gene at chromosome 3p25.1; the enzyme recycles biotin (vitamin B7) from biocytin, the product of biotin-dependent carboxylase breakdown is the enzyme responsible for regenerating free biotin from protein-bound forms in the diet and from normal cellular protein turnover. Without it, the body cannot recycle its biotin supply — a cofactor that four essential carboxylase enzymes depend on for amino acid catabolism, gluconeogenesis, and fatty acid synthesis. When biotinidase is absent or severely reduced, biotin deficiency accumulates regardless of dietary intake, because the bound form simply cannot be freed for reuse.

The rs398123138 variant is a 5-base pair deletion (c.1448_1452delGGATG) in exon 4 of BTD that shifts the reading frame at codon 483, producing a premature stop signal at position 509 (p.Gly503Aspfs*6). The final 41 amino acids of the mature biotinidase protein are replaced by 6 aberrant residues before translation terminates, eliminating the C-terminal domain critical for enzyme function. ClinVar classifies this variant as pathogenic for biotinidase deficiency22 biotinidase deficiency
OMIM 253260; autosomal recessive inborn error of biotin metabolism; combined incidence 1 in 61,067 newborns; carrier frequency approximately 1 in 120 with consensus from five independent clinical genetics laboratories.

The Mechanism

Biotinidase cleaves biocytin — the biotinyl-lysine product released during carboxylase protein turnover — to regenerate free biotin. Free biotin is then re-attached to the apocarboxylase enzymes that power four critical metabolic reactions: pyruvate carboxylase (gluconeogenesis), acetyl-CoA carboxylase (fatty acid synthesis), propionyl-CoA carboxylase (amino acid catabolism), and methylcrotonyl-CoA carboxylase (leucine catabolism). When biotinidase is absent, biocytin accumulates in urine, free biotin is progressively depleted, and all four carboxylases lose their cofactor. The frameshift in this variant destroys the C-terminal region of biotinidase, which structural studies suggest is essential for substrate binding and catalytic activity, resulting in complete loss of enzyme function — categorised as profound biotinidase deficiency (<10% of normal enzyme activity).

The inheritance pattern is autosomal recessive. One functional copy of BTD is sufficient to maintain normal biotin recycling; carriers with a single defective allele are clinically unaffected under normal conditions. Biallelic loss — two pathogenic BTD alleles (homozygous or compound heterozygous) — is required to produce the deficiency phenotype.

The Evidence

Biotinidase deficiency was first described in the early 1980s and neonatal screening has been universal in many countries since the mid-1990s33 universal in many countries since the mid-1990s
Newborn screening identifies biotinidase deficiency by enzyme activity assay on dried blood spot; normal activity is defined as 100%; profound deficiency <10%; partial deficiency 10–30%. Untreated profound deficiency typically presents between one week and ten years of age (mean 3.5 months) with neurological deterioration — seizures, hypotonia, developmental delay, alopecia, skin rash, and sensorineural hearing loss. Without treatment, the disorder is progressive and potentially fatal. With early biotin supplementation, the prognosis is excellent44 excellent
Wolf 2012 (PMID 22698809): two-decade NBS follow-up — all NBS-detected patients treated early are developmentally normal; late-treated patients who already had symptoms retain sensorineural hearing loss and optic atrophy even after biotin normalises.

The BTD c.1448_1452del frameshift has been observed in affected individuals with confirmed biotinidase deficiency and submitted to ClinVar by five independent laboratories including Baylor Genetics, Labcorp Genetics, CENTOGENE, Eurofins, and Counsyl — achieving 2-star "multiple submitters, no conflicts" review status. Allele frequency in population databases (gnomAD) is effectively zero, consistent with the extreme rarity expected for a pathogenic null allele in an autosomal recessive disorder with combined incidence of 1 in 61,067.

Practical Implications

For homozygotes or compound heterozygotes (two pathogenic BTD alleles): oral free biotin supplementation fully corrects the biochemical defect. Profound deficiency requires 5–10 mg/day of free D-biotin; partial deficiency (10–30% residual enzyme activity) is typically managed with 2.5–10 mg/day. Treatment is lifelong — biotinidase cannot be restored — but biotin at these pharmacologic doses has no known toxicity. Early diagnosis through newborn screening is critical: symptoms that develop before biotin is started (particularly sensorineural hearing loss) may be irreversible even after biotin normalises.

For heterozygous carriers, no supplementation is required. The single functional BTD copy maintains sufficient enzyme activity for normal biotin recycling under typical dietary conditions. The practical significance of carrier status is reproductive: two carrier parents face a 25% per-pregnancy risk of having an affected child.

Interactions

Biotinidase deficiency interacts directly with other BTD pathogenic variants in a compound heterozygous pattern. Related variants rs397507172, rs397507173, and rs397507174 are additional pathogenic alleles at the BTD locus; a carrier of c.1448_1452del who also carries one of these variants on the other chromosome would have biallelic BTD dysfunction and profound deficiency. The practical implication is that partner carrier testing should cover the full BTD coding sequence, not just this single variant, to accurately calculate offspring risk.

High-dose biotin supplementation (≥5 mg/day) as used in treatment can interfere with biotin-streptavidin immunoassays — a technology used in many commercial laboratory tests including thyroid hormones (TSH, free T4), cardiac troponins, and PTH. Patients on pharmacologic biotin should inform their treating physicians and pause biotin for 2–3 days before immunoassay- based blood tests to avoid spurious results.

Nutrient Interactions

biotin increased_need

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

Both BTD copies intact — normal biotinidase enzyme activity

You carry two copies of the reference allele at rs398123138. Both copies of your BTD gene are intact at this position, and your biotinidase enzyme can recycle biotin normally from dietary and cellular sources. You are not a carrier of this biotinidase deficiency-associated frameshift deletion. This genotype represents the vast majority of people worldwide; the deletion allele is vanishingly rare in all studied populations.

DI Carrier Carrier

Carrier of one pathogenic BTD deletion — no enzyme deficiency, but reproductive significance

Biotinidase deficiency is autosomal recessive, meaning two non-functional BTD alleles — on both chromosomes — are required to cause enzyme deficiency. A single intact copy maintains sufficient biotinidase activity for normal biotin metabolism throughout life. No biotin supplementation or dietary modification is warranted for carrier status alone.

The c.1448_1452del deletion destroys the C-terminal domain of biotinidase, creating a null allele with no residual enzyme function. In compound heterozygosity — this deletion on one chromosome and a different pathogenic BTD variant on the other — the result is functionally equivalent to homozygosity for null alleles, producing profound biotinidase deficiency. Partner carrier testing should ideally sequence the full BTD coding region, not just this single variant, to capture the full range of pathogenic alleles.

DD Homozygous Homozygous

Homozygous BTD deletion — biotinidase absent; lifelong biotin supplementation required

Profound biotinidase deficiency (BTD enzyme activity <10% of normal) typically presents between one week and ten years of life (mean 3.5 months) with seizures (often myoclonic), hypotonia, developmental delay, alopecia, eczematous skin rash, and sensorineural hearing loss. Optic atrophy and vision loss can occur with prolonged deficiency. Metabolic features include organic aciduria (3-methylcrotonylglycinuria, 3-hydroxyisovaleric aciduria) and lactic acidosis reflecting failure of the four carboxylase enzymes.

Oral free biotin completely corrects the biochemical defect by bypassing the recycling pathway — it provides exogenous free biotin that does not require biotinidase to release it. Treatment must use free biotin (D-biotin), not biotin supplements from protein-bound sources that require the very enzyme that is absent. Neurological deficits that developed before treatment are often irreversible, particularly sensorineural hearing loss and optic atrophy — underscoring the critical importance of newborn screening and early treatment initiation.

High-dose biotin therapy can interfere with biotin-streptavidin immunoassays (thyroid function tests, cardiac troponins, PTH, vitamin D assays) and should be paused 2–3 days before such tests.