NBIA Panel - Clinical Genetic Test - GTR

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NBIA Panel

Clinical Genetic Test

offered by

Genetic Services Laboratory

View lab's test page

GTR Test Accession: GTR000506324.6

CAP

INHERITED DISEASENERVOUS SYSTEMMETABOLIC DISEASE ... View more

Last updated in GTR: 2021-01-19

Last annual review date for the lab: 2024-07-22

At a Glance

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; ...

Conditions (9):

Neurodegeneration with brain iron accumulation; Deficiency of ferroxidase; Hereditary spastic paraplegia 35 more...

Genes (13):

ATP13A2 (1p36.13); C19orf12 (19q12); COASY (17q21.2); CP (3q24-25.1); DCAF17 (2q31.1) more...

Methods (2):

Molecular Genetics - Deletion/duplication analysis: Next-Generation (NGS)/Massively parallel sequencing (MPS); ...

Target population:

The target population for this test is patients suspected of …

Clinical validity:

Mutations in ATP13A2 are associated with Kufor-Rakeb syndrome, which is …

Clinical utility:

Establish or confirm diagnosis

Ordering Information

Offered by:

Genetic Services Laboratory
View lab's website
View lab's test page

Specimen Source:

Buccal swab
Cell culture
Cord blood
Fetal blood
Fibroblasts
Peripheral (whole) blood
Saliva
View specimen requirements

Who can order:

Genetic Counselor
Health Care Provider
Licensed Physician
Nurse Practitioner
Physician Assistant
Registered Nurse

CPT codes:

81479

**AMA CPT codes notice

Contact Policy:

Laboratory can only accept contact from health care providers. Patients/families are encouraged to discuss genetic testing options with their health care provider.

How to Order:

All samples should be shipped via overnight delivery at room temperature.
No weekend or holiday deliveries.
Label each specimen with the patient’s name, date of birth and date sample collected.
Send specimens with complete requisition and consent form, otherwise, specimen processing may be delayed.
Order URL

Test service:

Clinical Testing/Confirmation of Mutations Identified Previously
Confirmation of research findings

Test additional service:

Custom Prenatal Testing
Custom mutation-specific/Carrier testing

Test development:

Test developed by laboratory but exempt from FDA oversight (eg. NYS CLEP approved, offered within a hospital or clinic)

Informed consent required:

Pre-test genetic counseling required:

Decline to answer

Post-test genetic counseling required:

Decline to answer

Recommended fields not provided:

Test Order Code, Lab contact for this test, Test strategy

Conditions

Total conditions: 9

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 13

Gene	Associated Condition	Germline or Somatic	Allele (Lab-provided)	Variant in NCBI

Methodology

Total methods: 2

Method Category

Test method

Instrument *

Deletion/duplication analysis

Next-Generation (NGS)/Massively parallel sequencing (MPS)

Sequence analysis of the entire coding region

Next-Generation (NGS)/Massively parallel sequencing (MPS)

* Instrument: Not provided

Clinical Information

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; Pre-symptomatic; Risk Assessment; Screening

Clinical validity:

Mutations in ATP13A2 are associated with Kufor-Rakeb syndrome, which is characterized by juvenile-onset parkinsonism, dementia, supranuclear gaze palsy, pyramidal signs, visual hallucinations and oculogyric dystonic spasms. Some affected individuals have been described with evidence of brain iron accumulation in the caudate and putamen, however this not observed in all patients. … Mutations in ATP13A2 are associated with Kufor-Rakeb syndrome, which is characterized by juvenile-onset parkinsonism, dementia, supranuclear gaze palsy, pyramidal signs, visual hallucinations and oculogyric dystonic spasms. Some affected individuals have been described with evidence of brain iron accumulation in the caudate and putamen, however this not observed in all patients. ATP13A2 encodes for an ATPase that transports inorganic cations and other substrates across cell membranes, and is most strongly expressed in the brain. MPAN is caused by mutations in the C19orf12 gene, and is associated with motor neuronopathy, spasticity, dystonia, optic atrophy and neuropsychiatric abnormalities. Most patients also have cognitive decline. Onset of symptoms is typically in childhood or early adulthood, and the disorder is slowly progressive. Iron accumulation occurs in all patients and exhibits a distinctive pattern involving the globus pallidus and substantia nigra. C19orf12 encodes a protein that localizes to the mitochondria and is expressed most prominently in the brain, blood cells and adipocytes. Mutations in CP cause Aceruloplasminemia, which is associated with retinal degeneration, diabetes and neurological disease. Neurological manifestations can include facial and neck dystonia, blepharospasm, grimacing, tremors, chorea, gait ataxia and dysarthria. Age of onset ranges from early to late adulthood. Iron accumulation typically occurs in the striatum, thalamus and dentate nucleus of the brain, as well as visceral organs. Affected individuals also have low serum copper and iron, and high serum ferritin. CP encodes for the precursor to ceruloplasmin, which transports copper and also plays an important role in iron mobilization. Woodhouse-Sakati syndrome is associated with mutations in DCAF17, and is characterized by hypogonadism, partial alopecia, diabetes, intellectual disability, deafness and a progressive extrapyramidal disorder. Brain iron accumulation occurs in the globus pallidus, substantia nigra and other regions of the basal ganglia, and white matter disease is also frequently observed. DCAF17 encodes a nucleolar protein of unknown function. FAHN is caused by mutation in the FA2H gene, and is associated with spasticity, ataxia and dystonia. Age of onset is typically in childhood, and affected individuals typically develop optic atrophy and oculomotor abnormalities during the early stages of disease, and progressive intellectual impairment and seizures in the later stages. Iron accumulation occurs in the globus pallidus and substantia nigra. Progressive white matter changes and cerebellar and brain stem atrophy are also observed. FA2H encodes for fatty acid 2-hydroxylase, which alpha-hydroxylates fatty acids, which are then incorporated into several diverse lipid species. Mutations in FTL cause neuroferritinopathy, which is characterized by extrapyramidal features similar to Huntington disease or parkinsonism. The average age of onset is 39 years. Additional symptoms can include tremor, cerebellar ataxia, and cognitive decline. Affected individuals typically have low serum ferritin levels, and brain MRI findings consistent with excess iron storage and cystic changes involving the globus pallidus and the putamen. FTL encodes for a subunit of ferritin, and mutations in FTL cause abnormally shaped ferritin molecules and aggregation of ferritin and associated iron molecules in the brain. PKAN (previously known as Hallervorden-Spatz syndrome) is caused by mutations in PANK2. There is wide phenotypic variability, including classic PKAN and atypical PKAN. Classic PKAN is associated with early onset (3-4 years of age), rapid progression, impaired gait, restricted visual fields, dystonia, dysarthria, spasticity, retinopathy, and possible cognitive impairment. Atypical PKAN has a mean age of onset of 13-14, slow progression, speech difficulties, neurobehavioral changes, Parkinson-like syndrome, spasticity, hyperreflexia and possible cognitive impairment. Most individuals with PANK2 mutations show brain iron accumulation, which is specific to the globus pallidus and substantia nigra and appears as the “eye of the tiger” sign. PANK2 is a key regulatory enzyme in several metabolic pathways of Coenzyme A biosynthesis. PLAN is caused by mutations in PLA2G6 and is associated with a continuum of three phenotypes: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-associated dystonia-parkinsonism. Patients with INAD and atypical NAD both have hypointensity of the globus pallidus on T2-weighted MRI, indicating iron accumulation. INAD patients also have cerebellar gliosis, white matter abnormalities and a thin, vertically oriented corpus callosum. Patients with PLA2G6-associated dystonia-parkinsonism may show iron accumulation in the globus pallidus, substantia nigra and/or striatum, however this is often not evident until late in the disease course. PLA2G6 encodes for an enzyme that plays an important role in cell membrane homeostasis and phospholipid metabolism, and PLA2G6 mutations gene may result in phospholipase A2 dysfunction critical in brain iron regulation and normal axonal pathology. Mutations in WDR45 cause BPAN, which is associated with global developmental delay in childhood and sudden onset of progressive dystonia-parkinsonism and dementia in adolescence or adulthood. Brain iron accumulation occurs in the globus pallidus and substantia nigra. WDR45 encodes for a protein which has an important role in autophagy, and mutations in the WDR45 gene leads to an accumulation of aberrant early autophagic structures. View more

View citations (15)

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Curtis AR, et al. Nat Genet. 2001;28(4):350-4. doi:10.1038/ng571. PMID: 11438811.
A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Zhou B, et al. Nat Genet. 2001;28(4):345-9. doi:10.1038/ng572. PMID: 11479594.
Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. Hayflick SJ, et al. N Engl J Med. 2003;348(1):33-40. doi:10.1056/NEJMoa020817. PMID: 12510040.
Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. Levi S, et al. Best Pract Res Clin Haematol. 2005;18(2):265-76. doi:10.1016/j.beha.2004.08.021. PMID: 15737889.
Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38(10):1184-91. doi:10.1038/ng1884. Epub 2006 Sep 10. PMID: 16964263.
Chinnery PF, Crompton DE, Birchall D, Jackson MJ, Coulthard A, Lombès A, Quinn N, Wills A, Fletcher N, Mottershead JP, Cooper P, Kellett M, Bates D, Burn J. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain. 2007;130(Pt 1):110-9. doi:10.1093/brain/awl319. Epub 2006 Dec 02. PMID: 17142829.
Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, Bavi P, Kaya N, Colak D, Khalak H, Baltus A, Peterlin B, Danda S, Bhatia KP, Schneider SA, Sakati N, Walsh CA, Al-Mohanna F, Meyer B, Alkuraya FS. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008;83(6):684-91. doi:10.1016/j.ajhg.2008.10.018. Epub 2008 Nov 20. PMID: 19026396.
Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Hartig MB, et al. Am J Hum Genet. 2011;89(4):543-50. doi:10.1016/j.ajhg.2011.09.007. PMID: 21981780.
Kruer MC, Paudel R, Wagoner W, Sanford L, Kara E, Gregory A, Foltynie T, Lees A, Bhatia K, Hardy J, Hayflick SJ, Houlden H. Analysis of ATP13A2 in large neurodegeneration with brain iron accumulation (NBIA) and dystonia-parkinsonism cohorts. Neurosci Lett. 2012;523(1):35-8. doi:10.1016/j.neulet.2012.06.036. Epub 2012 Jun 25. PMID: 22743658.
Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, Egel RT, Subramony SH, Goldman JG, Berry-Kravis E, Foulds NC, Hammans SR, Desguerre I, Rodriguez D, Wilson C, Diedrich A, Green S, Tran H, Reese L, Woltjer RL, Hayflick SJ. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013;80(3):268-75. doi:10.1212/WNL.0b013e31827e07be. Epub 2012 Dec 26. PMID: 23269600.
Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. 2013;45(4):445-9, 449e1. doi:10.1038/ng.2562. Epub 2013 Feb 24. PMID: 23435086.
Gregory A, Hayflick S. Neurodegeneration with Brain Iron Accumulation Disorders Overview. 2013 Feb 28 [updated 2019 Oct 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 23447832.
Gregory A. PLA2G6-Associated Neurodegeneration.: GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle., 2008, Jun 18 [Updated 2012 Apr 19].
Miyajima H. Aceruloplasminemia.: GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle., 2003, Aug 12 [Updated 2013, Apr 18].
https://www.ncbi.nlm.nih.gov/books/NBK121988

Clinical utility:

Establish or confirm diagnosis

View citations (11)

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Curtis AR, et al. Nat Genet. 2001;28(4):350-4. doi:10.1038/ng571. PMID: 11438811.
A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Zhou B, et al. Nat Genet. 2001;28(4):345-9. doi:10.1038/ng572. PMID: 11479594.
Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. Hayflick SJ, et al. N Engl J Med. 2003;348(1):33-40. doi:10.1056/NEJMoa020817. PMID: 12510040.
Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. Levi S, et al. Best Pract Res Clin Haematol. 2005;18(2):265-76. doi:10.1016/j.beha.2004.08.021. PMID: 15737889.
Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38(10):1184-91. doi:10.1038/ng1884. Epub 2006 Sep 10. PMID: 16964263.
Chinnery PF, Crompton DE, Birchall D, Jackson MJ, Coulthard A, Lombès A, Quinn N, Wills A, Fletcher N, Mottershead JP, Cooper P, Kellett M, Bates D, Burn J. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain. 2007;130(Pt 1):110-9. doi:10.1093/brain/awl319. Epub 2006 Dec 02. PMID: 17142829.
Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, Bavi P, Kaya N, Colak D, Khalak H, Baltus A, Peterlin B, Danda S, Bhatia KP, Schneider SA, Sakati N, Walsh CA, Al-Mohanna F, Meyer B, Alkuraya FS. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008;83(6):684-91. doi:10.1016/j.ajhg.2008.10.018. Epub 2008 Nov 20. PMID: 19026396.
Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Hartig MB, et al. Am J Hum Genet. 2011;89(4):543-50. doi:10.1016/j.ajhg.2011.09.007. PMID: 21981780.
Kruer MC, Paudel R, Wagoner W, Sanford L, Kara E, Gregory A, Foltynie T, Lees A, Bhatia K, Hardy J, Hayflick SJ, Houlden H. Analysis of ATP13A2 in large neurodegeneration with brain iron accumulation (NBIA) and dystonia-parkinsonism cohorts. Neurosci Lett. 2012;523(1):35-8. doi:10.1016/j.neulet.2012.06.036. Epub 2012 Jun 25. PMID: 22743658.
Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, Egel RT, Subramony SH, Goldman JG, Berry-Kravis E, Foulds NC, Hammans SR, Desguerre I, Rodriguez D, Wilson C, Diedrich A, Green S, Tran H, Reese L, Woltjer RL, Hayflick SJ. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013;80(3):268-75. doi:10.1212/WNL.0b013e31827e07be. Epub 2012 Dec 26. PMID: 23269600.
Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. 2013;45(4):445-9, 449e1. doi:10.1038/ng.2562. Epub 2013 Feb 24. PMID: 23435086.

Target population:

The target population for this test is patients suspected of having a diagnosis of NBIA.

Variant Interpretation:

What is the protocol for interpreting a variation as a VUS?
Variants are identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors.

Will the lab re-contact the ordering physician if variant interpretation changes?
Yes.

Research:

Is research allowed on the sample after clinical testing is complete?
http://dnatesting.uchicago.edu/research-consent-form

Recommended fields not provided:

Are family members with defined clinical status recruited to assess significance of VUS without charge?, Sample negative report, Sample positive report

Technical Information

Availability:

Tests performed
Entire test performed in-house

Analytical Validity:

Analytical Sensitivity 99-100% Accuracy 100% Precision 100%

Assay limitations:

This assay covers the coding and immediate flanking regions of the included genes. Variants in the promoter region and in other non-coding regions will not be detected. Variants that occur within regions of high homology and/or repetitiveness may not be detected due to issues with alignment. The technical sensitivity of … View more

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Formal PT program

PT Provider:
American College of Medical Genetics / College of American Pathologists, ACMG/CAP

VUS:

Software used to interpret novel variations
A custom collection of bioinformatics tools

Laboratory's policy on reporting novel variations
All novel and/or potentially pathogenic variants are confirmed by Sanger sequencing

Recommended fields not provided:

Test Confirmation, Citations to support assay limitations, Description of internal test validation method, Citations for Analytical validity, Description of PT method, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Category: FDA exercises enforcement discretion

Additional Information

Reviews:

Genereviews

PubMed Clinical Queries

Clinical resources:

Consumer resources:

NCATS Office of Rare Diseases Research (GARD)

MedlinePlus

IMPORTANT NOTE: NIH does not independently verify information submitted to GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in GTR. GTR is not a substitute for medical advice. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.