Neurodegeneration with Brain Iron Accumulation and Infantile Neuroaxonal Dystrophy Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
2695 AP4M1 81479,81479 Order Options and Pricing
ATP13A2 81479,81479
C19orf12 81479,81479
COASY 81479,81479
CP 81479,81479
CRAT 81479,81479
DCAF17 81479,81479
FA2H 81479,81479
FTL 81479,81479
GTPBP2 81479,81479
NALCN 81479,81479
PANK2 81479,81479
PLA2G6 81479,81479
REPS1 81479,81479
SCP2 81479,81479
WDR45 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
2695Genes x (16)81479 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous neurologic disorder characterized by progressive dystonia and dysarthria, parkinsonism, and spasticity. Optic atrophy or retinal degeneration are common symptoms. Neuropsychiatric abnormalities occur in some subtypes. Generalized cerebral atrophy and cerebellar atrophy also frequently present. The age of onset is from infancy to late adulthood with variable progression.

The hallmark feature of NBIA in brain MRI is excess iron accumulation in the basal ganglia, particularly in the globus pallidus and substantia nigra. Pathogenic changes also include Lewy bodies, axonal swellings and hyperphosphorylated tau in certain types of NBIA. The disease is primarily suspected in a patient when brain MRI findings suggest abnormal brain iron accumulation. Different disease types and their associated genes are recognized (Schneider and Bhatia. 2013. PubMed ID: 23212724; Schneider et al. 2013. PubMed ID: 23814539; Arber et al. 2016. PubMed ID: 25870938; Drecourt et al. 2018. PubMed ID: 29395073; Lee et al. 2018. PubMed ID: 29371252).

Infantile neuroaxonal dystrophy (INAD) has early onset from six months to three years with developmental regression, hypotonia, visual disturbance, progressive spastic tetraparesis and motor and mental retardation (Salih et al. 2013. PubMed ID: 24130795; Köroglu et al. 2013. PubMed ID: 23749988; Levi and Finazzi. 2014. PubMed ID: 24847269). Variants in PLA2G6 and NALCN are causative for INAD.

In this NextGen Panel, we sequence genes in which pathogenic variants have been reported in the literature to be causative for NBIA and INAD. This panel covers different types of NBIA disorders and certain other disorders which share phenotype with NBIA. The most important types are listed below:

(1) Pantothenate kinase-associated neurodegeneration (PKAN): also known as Hallervorden-Spatz disease. PKAN is the most common type of NBIA and occurs in approximate two-thirds of NBIA patients.

(2) PLA2G6-associated neurodegeneration (PLAN)

(3) Mitochondrial membrane protein-associated neurodegeneration (MPAN)

(4) Beta-propeller protein-associated neurodegeneration (BPAN)

(5) Fatty acid hydroxylase-associated neurodegeneration (FAHN)

(6) Kufor-Rakeb syndrome, also called Parkinson disease 9.

(7) Neuroferritinopathy

(8) Aceruloplasminemia

(9) COASY protein-associated neurodegeneration

(10) Woodhouse-Sakati syndrome

(11) Infantile neuroaxonal dystrophy (INAD)

Genetics

This panel for NBIA and INAD contains 16 genes: PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, DCAF17, GTPBP2, CRAT, REPS1, SCP2, AP4M1 and NALCN. Of these, variants in PLA2G6 and NALCN are causative for INAD, and the remainder causative for NBIA. The vast majority of pathogenic variants in genes in this panel are inherited in an autosomal recessive manner. The exceptions are WDR45 pathogenic variants which are inherited in an X-linked dominant manner and FTL pathogenic variants which are inherited in an autosomal dominant manner. The most important genes in this panel are described briefly below:

PANK2 encodes pantothenate kinase 2 which is an essential regulatory enzyme in CoA biosynthesis, and is located in the mitochondria. Pathogenic variants in PANK2 are causative for pantothenate kinase-associated neurodegeneration (PKAN) which is inherited in an autosomal recessive manner (Leoni et al. 2012. PubMed ID: 22221393; Lee et al. 2016. PubMed ID: 26828213).

PLA2G6 encodes a calcium-independent phospholipases A2 group VI which catalyzes the hydrolysis of the sn-2 acyl-ester bonds in phospholipids. Pathogenic variants in PANK2 are causative for INAD, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism, which are all inherited in an autosomal recessive manner (Salih et al. 2013. PubMed ID: 24130795; Romani et al. 2015. PubMed ID: 25164370).

C19orf12 encodes chromosome 19 open reading frame 12 located on the outer mitochondrial membrane. Pathogenic variants in C19orf12 are causative for mitochondrial membrane protein-associated neurodegeneration (MPAN), which is primarily inherited in an autosomal recessive manner (Hogarth et al. 2013. PubMed ID: 23269600; Tschentscher et al. 2015. PubMed ID: 25592411). However, autosomal dominant inheritance in this disorder has also been documented (Gregory et al. 2019. PubMed ID: 31087512).

WDR45 encodes WD repeat-containing protein. Pathogenic variants in WDR45 are causative for beta-propeller protein-associated neurodegeneration (BPAN), which is inherited in an X-linked dominant manner. The majority of cases are females, however, a few male patients have been reported (Haack et al. 2012. PubMed ID). Most pathogenic variants occur de novo (Haack et al. 2012. PubMed ID: 23176820; Hayflick et al. 2013. PubMed ID: 23687123).

FA2H encodes Fatty acid 2 hydroxylase. Pathogenic variants in FA2H are causative for Fatty acid hydroxylase-associated neurodegeneration (FAHN), which is inherited in an autosomal recessive manner (Arber et al. 2016. PubMed ID: 25870938).

ATP13A2 encodes ATPase type 13A2. Pathogenic variants in ATP13A2 are causative for Kufor-Rakeb syndrome, which is inherited in an autosomal recessive manner (Kruer et al. 2012. PubMed ID: 22743658).

FTL encodes ferritin light chain which aids mineralization within the ferritin structure. Pathogenic variants in FTL are causative for neuroferritinopathy, which is inherited in an autosomal dominant manner (Keogh et al. 2012. PubMed ID: 22278127).

CP encodes ceruloplasmin, which is involved in cellular iron export. Pathogenic variants in CP are causative for aceruloplasminemia, which is inherited in an autosomal recessive manner (Kono and Miyajima. 2006. PubMed ID: 16629161).

COASY encodes coenzyme A synthase, which is in the same metabolic pathway as PANK2 and is a bifunctional enzyme catalyzing the final two steps of CoA synthesis. Pathogenic variants in COASY are causative for COASY protein-associated neurodegeneration (CoPAN), which is inherited in an autosomal recessive manner (Dusi et al. 2014. PubMed ID: 24360804).

DCAF17 encodes DDB1-and-CUL4-associated factor 17. Pathogenic variants in DCAF17 are causative for Woodhouse-Sakati syndrome, which is inherited in an autosomal recessive manner (Alazami et al. 2008. PubMed ID: 19026396).

NALCN encodes nonselective sodium leak channel. Nonsense pathogenic variants in NALCN are causative for INAD, which is inherited in an autosomal recessive manner (Köroglu et al. 2013. PubMed ID: 23749988).

See individual gene test descriptions for more information on molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in PANK2 account for 35%-50% of Neurodegeneration with brain iron accumulation, PLA2G6 for 10%, C19orf12 for 6-10%, WDR45 for 1-2%, while pathogenic variants found in other genes in this panel are rare (Gregory and Hayflick 2014. PubMed ID:23447832).

To date, large deletions or duplications have been reported in only a few genes in this panel. Large deletions/duplications have been reported in PLA2G6.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this panel include patients suspected to have any type of NBIA or INAD.

Genes

Official Gene Symbol OMIM ID
AP4M1 602296
ATP13A2 610513
C19orf12 614297
COASY 609855
CP 117700
CRAT 600184
DCAF17 612515
FA2H 611026
FTL 134790
GTPBP2 607434
NALCN 611549
PANK2 606157
PLA2G6 603604
REPS1 614825
SCP2 184755
WDR45 300526
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Alazami et al. 2008. PubMed ID: 19026396
  • Arber et al. 2016. PubMed ID: 25870938
  • Drecourt et al. 2018. PubMed ID: 29395073
  • Dusi et al. 2014. PubMed ID: 24360804
  • Gregory and Hayflick. 2014. PubMed ID: 23447832
  • Gregory et al. 2019. PubMed ID: 31087512
  • Haack et al. 2012. PubMed ID: 23176820
  • Hayflick et al. 2013. PubMed ID: 23687123
  • Hogarth et al. 2013. PubMed ID: 23269600
  • Keogh et al. 2012. PubMed ID: 22278127
  • Kono and Miyajima. 2006. PubMed ID: 16629161
  • K├Âroglu et al. 2013. PubMed ID: 23749988
  • Kruer et al. 2012. PubMed ID: 22743658
  • Lee et al. 2016. PubMed ID: 26828213
  • Lee et al. 2018. PubMed ID: 29371252
  • Leoni et al. 2012. PubMed ID: 22221393
  • Levi and Finazzi 2014. PubMed ID: 24847269
  • Romani et al. 2015. PubMed ID: 25164370
  • Salih et al. 2013. PubMed ID: 24130795
  • Schneider and Bhatia 2013. PubMed ID: 23212724
  • Schneider et al. 2013. PubMed ID: 23814539
  • Tschentscher et al. 2015. PubMed ID: 25592411

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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