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  • Test code: 06194
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Biotinidase Deficiency Test

Test description

The Invitae Biotinidase Deficiency Test analyzes the gene BTD, which is associated with biotinidase deficiency. This test is useful for the diagnosis of patients in whom biotinidase deficiency is suspected due to clinical symptoms, abnormal newborn screening results, or biochemical findings.

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Primary panel (1 gene)

Alternative tests to consider

These panels have been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. They can be ordered at no additional cost.

  • biotinidase deficiency
    • partial biotinidase deficiency
    • profound biotinidase deficiency

Profound biotinidase deficiency is generally seen in patients with less than 10% of residual biotinidase activity. Untreated patients with profound biotinidase deficiency can have hypotonia, seizures, alopecia, eczema, metabolic acidosis, and developmental delay. Over time, untreated patients may develop sensorineural hearing loss, candidiasis, ataxia, conjunctivitis, and visual problems such as optic atrophy. Early treatment with pharmacologic doses of biotin is important to prevent irreversible neurologic damage. With early intervention and treatment, patients generally remain asymptomatic.

Partial biotinidase deficiency is the most common clinical subtype of biotinidase deficiency. Many patients with partial biotinidase deficiency have been picked up on newborn screening and remain asymptomatic. Those with symptoms, however, may have intermittent hypotonia, skin rashes, or alopecia during times of prolonged intercurrent illness. Partial biotinidase deficiency is generally seen in patients with 10%–30% of residual biotinidase activity.

Biotinidase deficiency is an enzyme deficiency that affects the recycling of the coenzyme biotin, a water-soluble B vitamin. If untreated, this disorder can result in deficiencies of the four biotin-dependent carboxylases: acetyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase, and pyruvate carboxylase. A biochemical feature of biotinidase deficiency is the abnormal elevation of urine organic acids, including 3-hydroxyisovaleric acid, lactic acid, 3-hydroxypropionic acid, methylcitric acid, 3-methylcrotonylglycine, propionylglycine, and tiglylglycine. Propionylcarnitine (C3) and 3-hydroxyisovalerylcarnitine (C5-OH) can also be elevated. Serum biotinidase activity will be low. Currently, most patients with biotinidase deficiency are identified through newborn screening.

Approximately 100% of patients with symptoms that are consistent with biotinidase deficiency and a biochemical diagnosis of biotinidase deficiency will have two pathogenic mutations in the BTD gene.

Symptoms and biochemical diagnosis:

  • elevated 3-hydroxyisovaleric acid and lactic acid in the urine, with or without elevated levels of:
    • 3-hydroxypropionic acid
    • methylcitric acid
    • 3-methylcrotonylglycine
    • propionylglycine
    • tiglylglycine
  • low serum biotinidase activity

Biotinidase deficiency is inherited in an autosomal recessive pattern.

Profound biotinidase deficiency is a fully penetrant disorder; symptom onset ranges from one week to ten years, with an average age of onset of 3.5 months. Only some patients with partial biotinidase deficiency will have symptoms; those who do may not present until adulthood. Because patients with biotinidase deficiency can have a wide variability in clinical and biochemical symptoms, molecular testing may be warranted in suspected patients who lack the classic organic aciduria.

The worldwide prevalence for biotinidase deficiency is 1 in 60,000. Partial biotinidase deficiency has a birth incidence of roughly 1 in 129,500. Profound biotinidase deficiency has a birth incidence of 1 in 112,271. The birth incidence of both partial and profound biotinidase deficiency has been estimated in several subpopulations as follows:

  • Turkey: 1 in 7,116
  • United Arab Emirates: 1 in 8,300
  • Brazil: 1 in 9,000
  • Hungary: 1 in 18,700

This panel may be appropriate for:

  • patients who have low biotinidase enzyme activity on NBS or low serum biotinidase activity, with or without elevated C5-OH or C3 on acylcarnitine analysis
  • patients who have clinical features suggestive of biotinidase deficiency, including eczema, alopecia, conjunctivitis, and candidiasis in addition to developmental delay, hypotonia, metabolic acidosis, and seizures

For considerations for testing please refer to:

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
BTD NM_000060.3