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KIF1A-Related Disorders via the KIF1A Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
5419 KIF1A$690.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the KIF1A gene reported to date can be detected by sequencing.

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Clinical Features

The KIF1A gene has been associated with a spectrum of disorders which include: mental retardation autosomal dominant 9 (MRD9), spastic paraplegia 30 (SPG30) and hereditary sensory neuropathy IIC (HSNIIC).

MRD9 is a disorder characterized by intellectual disability associated with adaptive behavior impairments. The variable features include delayed speech development, microcephaly, ataxia, hypotonia, progressive spastic paraparesis and peripheral neuropathy. MRD9 patients typically have onset of disease in the first years of life (Hamdan et al. 2011. PubMed ID: 21376300; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038).

SPG30 is a neurodegenerative disorder with onset of a progressive weakness and stiffness in the lower limbs in the first or second decades. The severity of symptoms and rate of progression are quite variable. The weakness and spasticity may spread to arms and some patients may have bladder symptoms (Klebe et al. 2006. PubMed ID: 16434418; Erlich et al. 2011; Klebe et al. 2012. PubMed ID: 22258533; Ylikallio et al. 2015. PubMed ID: 25585697).

HSNIIC is a type of sensory neuropathy characterized by distal sensory loss leading to ulceration and amputation of the digits. The onset of the disease is usually in the first decade. Some HSNIIC patients may also develop distal muscle weakness primarily in the lower limbs (Rivière et al. 2011. PubMed ID: 21820098).

Genetics

KIF1A encodes kinesin family member 1A, which functions as an anterograde motor protein to transport dense core vesicle (DCVs) along microtubules to the pre- and post-synaptic regions. KIF1A dysfunction results in a reduction of DCVs at synapses and its accumulation in the cell body, leading to neuronal death (Lo et al. 2011. PubMed ID: 21256924).

To date, in the KIF1A gene only missense and frameshift variants have been reported to cause disease (Human Gene Mutation Database). Missense pathogenic variants predominate in cases of MRD9 and SPG30; all the reported pathogenic variants for HSANIIC are small deletions or insertions that cause a frameshift (Rivière et al. 2011. PubMed ID: 21820098). Pathogenic variants identified so far for MRD9 are de novo (Hamdan et al. 2011. PubMed ID: 21376300; Lee et al. 2015. PubMed ID: 25265257; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038; Ohba et al. 2015. PubMed ID: 26354034). For HSNIIC, the inheritance mode in the reported families is consistent with autosomal recessive inheritance (Rivière et al. 2011. PubMed ID: 21820098). SPG30 is typically inherited in an autosomal recessive manner, however, autosomal dominant cases have been reported recently (Iqbal et al. 2017. PubMed ID: 28362824).

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for regions not captured or with insufficient number of sequence reads. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

This test provides full coverage of all coding exons of the KIF1A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Patients with clinical symptoms consistent with KIF1A-related disorders are candidates for this test. Testing is also indicated for family members of patients who have known KIF1A pathogenic variants.

Gene

Official Gene Symbol OMIM ID
KIF1A 601255
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Complex Hereditary Spastic Paraplegia Sequencing Panel with CNV Detection
Comprehensive Neuropathy Sequencing Panel
Hereditary Sensory and Autonomic Neuropathy Sequencing Panel
Hereditary Spastic Paraplegia Comprehensive Sequencing Panel with CNV Detection
Pure Hereditary Spastic Paraplegia Sequencing Panel with CNV Detection

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Erlich et al. 2011. PubMed ID: 21487076
  • Esmaeeli Nieh et al. 2015. PubMed ID: 26125038
  • Hamdan et al. 2011. PubMed ID: 21376300
  • Human Gene Mutation Database (Bio-base).
  • Iqbal et al. 2017. PubMed ID: 28362824
  • Klebe et al. 2006. PubMed ID: 16434418
  • Klebe et al. 2012. PubMed ID: 22258533
  • Lee et al. 2015. PubMed ID: 25265257
  • Lo et al. 2011. PubMed ID: 21256924
  • Ohba et al. 2015. PubMed ID: 26354034
  • Rivière et al. 2011. PubMed ID: 21820098
  • Ylikallio et al. 2015. PubMed ID: 25585697
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TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

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Ordering Options


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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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