Background:
Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The age of onset ranges from infancy to late adulthood, and the rate of progression varies. Cognitive decline occurs in some subtypes, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding in some subtypes. The diagnosis is usually suspected with findings of brain iron accumulation on MRI. However, both clinical findings and molecular genetic testing establish the diagnosis of specific subtypes.
Our panel is the most comprehensive clinical NBIA testing panel currently available. It includes genes associated with well-described NBIA disorders, as well as genes associated with new emerging phenotypes and related disorders. The results of each NBIA panel are reviewed by Dr. Susan Hayflick, who discovered many of these genes, and provides consultation on NBIA disorders to physicians around the world.
Reasons for Referral:
- Confirmation of a suspected clinical diagnosis in patients with the hallmark findings of NBIA.
- Further assessment of patients with clinical diagnosis of idiopathic NBIA who have had mutations ruled out in other genes.
Methodology:
Next generation sequencing will analyze the exons or coding regions of 23 NBIA-associated genes using Illumina NextSeq 500/550 technology. Samples are prepared using hybridization probes to enrich exonic regions. This assay does not assess regions of insufficient coverage, introns and promoter regions; pseudogenes; where the reference genome is inaccurate or contains gaps and insertions; and regions of high GC or polynucleotide repeats, but may contain variants that impact gene function.
Exon-level deletion/duplication analysis is performed by running the same NGS data through the Genome Analysis Toolkit (GATK) Germline CNV best practices pipeline from a GATK version. The pipeline has been validated to detect deletion and duplication events as large as full chromosomes and as small as three exons. Detection of events involving one or two exons may occur but are not guaranteed within our validated parameters. If deemed reportable, deletions and duplications of <3 exons or with lower quality scores may be confirmed by orthogonal methods. Additionally, this assay is unable to detect exon 7 deletions in CIA01.
The 23 NBIA-associated genes are listed below:
| ATP13A2 |
C19orf12 |
CIA01 |
COASY |
CP |
DCAF17 |
FA2H |
| FTL |
FUCA1 |
KIF1A |
KMT2B (MLL4)
|
MECR |
PANK2 |
PLA2G6 |
| PSEN1 |
REPS1
|
SCP2 |
SLC39A14 |
SQSTM1
|
TRIM32 |
UBTF |
| VPS13A |
WDR45 |
|
|
|
|
|
Specimen Requirements:
Blood: EDTA or ACD (Solution A or B):
- Adult: 5 mL
- Child: 5 mL
- Infant: 2-3 mL
Saliva: 2 ORAgene™ Saliva Collection Kits (OGR-500) used according to manufacturer instructions. Please contact KDL Client Services for a Saliva Collection Kit for patients that cannot provide a blood sample.
Assisted Saliva: 4 ORAgene™ Assisted Saliva Collection Kits (OGR-575) used according to manufacturer instructions. Please contact KDL Client Services for an Assisted Saliva Collection Kit for patients that cannot provide a blood sample.
DNA: 7-10µg at a minimum of 60-100ng/µL (DNA must be extracted in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or CMS)
For routine testing of blood and saliva (or DNA extracted from them), KDL does NOT accept samples from patients within two (2) weeks of a packed cell/platelet transfusion or within four (4) weeks of a whole blood transfusion. For extraordinary circumstances, where testing must be performed outside of the above windows, please contact our lab.
A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES. Please include detailed clinical information, including ethnicity, clinical history, and family history.
Test Performed (Days):
Weekly
Turn Around Time:
6-8 weeks
Shipment Sensitivity Requirements:
Package and ship specimen to remain cold, but not frozen.
Ship via overnight express, using the FedEx priority overnight label provided.
Contact Client Services for shipping kits and instructions at (855) 535-1522.
References:
- Gregory A. and Hayflick S., 2014. GeneReviews: http://www.ncbi.nlm.nih.gov/books/NBK121988/
- Maio N., Orbach R., Zaharieva I., Töpf A., Donkervoort S., Munot P., Mueller J., Wilis T., Verma S, Peric S., Krishnakumar D., Sudhakar S., Foley A.R., Silverstein S., Douglas G., Pais L., DiTroia S., Grunseich C., Hu Y., Sewry C., Sarkozy A., Straub V., Muntoni F, Rouault T., Bönnemann C.G. Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes. MedRxiv. 2020 Dec 20. Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1
Additional Info: