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  • Test code: 03406
  • 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 Neurodegeneration with Brain Iron Accumulation Panel

Test description

The Invitae Neurodegeneration with Brain Iron Accumulation Panel analyzes up to 14 genes that are associated with neurodegeneration with brain iron accumulation (NBIA), which is characterized by accumulation of iron in the brain and results in progressive neurological deterioration (characterized by dystonia, rigidity, ataxia, and spasticity) and vision loss. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for NBIA.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (11 genes)

ATP13A2 C19orf12 COASY CP DCAF17 FTL FUCA1 PANK2 PLA2G6 SQSTM1 WDR45

Add-on Preliminary-evidence Genes for Neurodegeneration with Brain Iron Accumulation (3 genes)

In addition to the primary panel, clinicians can also choose to include three genes that have preliminary evidence of association with NBIA. At this time, the association of these three genes with NBIA remains preliminary. However, some clinicians may wish to include genes that may prove to be clinically significant in the future. Visit our Preliminary-evidence genes page to learn more.

FA2H KIF1A TRIM32

  • neurodegeneration with brain iron accumulation (NBIA)
  • at least 10 clinical subtypes are recognized:
    • aceruloplasminemia (CP)
    • beta-propeller protein-associated (WDR45)
    • CoPAN (COASY)
    • fatty acid hydroxylase-associated neurodegeneration (FA2H)
    • Kufor-Rakeb syndrome (ATP13A2)
    • mitochondrial membrane protein-associated neurodegeneration (C19orf12)
    • neuroferritinopathy (FTL)
    • pantothenate kinase-associated neurodegeneration (PANK2)
    • PLA2G6-associated neurodegeneration (PLA2G6)
    • Woodhouse-Sakati syndrome (DCAF17)

Neurodegeneration with brain iron accumulation (NBIA) is a set of conditions that have overlapping features that are all caused by the accumulation of iron in the basal ganglia of the brain. The accumulation of iron causes a progressive neurodegenerative condition that is characterized by a combination of neurological problems including dystonia, rigidity, ataxia, and spasticity, often accompanied by optic nerve atrophy or retinal degeneration. In addition to these general symptoms, which are shared across the NBIAs, there are 10 distinct subtypes which exhibit several additional features including psycho-social difficulties, speech decline, cognitive decline, diabetes, and alopecia. Age of onset may vary from early infancy to late adulthood. The rate of disease progression is variable, but is usually associated with age of onset (earlier onset tends to correlate with more severe disease progression).

The genes included in this panel are expected to be responsible for at least 62-70% of NBIA. Variants in the PANK2 gene are thought to cause about 35-50% of all NBIA, PLA2G6 approximately 20%, C19orf12 about 6-10%, and WDR45 about 1-2%. The remaining genes have been reported so rarely that their individual contributions to the overall burden of NBIA are uncertain. About 30% of NBIA remains idiopathic.

NBIA is typically inherited in an autosomal recessive pattern;however, there are two known exceptions. FTL has been reported to cause autosomal dominant NBIA, and WDR45 is reported to cause X-Linked dominant NBIA with reported disease-causing variants occurring de novo in affected individuals.

NBIA is believed to be completely penetrant.

Prevalence is estimated at 1-3 per million, with the individual subtypes being uncertain but very rare.

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
ATP13A2 NM_022089.3
C19orf12 NM_001031726.3
COASY NM_025233.6
CP NM_000096.3
DCAF17 NM_025000.3
FA2H NM_024306.4
FTL NM_000146.3
FUCA1 NM_000147.4
KIF1A NM_004321.6
PANK2 NM_153638.2
PLA2G6 NM_003560.2
SQSTM1 NM_003900.4
TRIM32 NM_012210.3
WDR45 NM_007075.3