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Hypomyelinating Leukodystrophy 7, with or without Oligodontia and/or Hypogonadotropic Hypogonadism via the POLR3A Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
15435 POLR3A 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15435POLR3A81479 81479(x2) $890 Order Options and Pricing

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

POLR3A-related hypomyelinating leukodystrophy is a rare neurological disorder with onset between 1 and 12 years old. Major symptoms include tremor-ataxia, spasticity, cerebellar signs, upper motor neuron signs, hypodontia, delayed puberty, hypogonadotropic hypogonadism and cognitive regression. Minor features include developmental delay, seizure, peripheral neuropathy, and decreased vibratory and positional sense. Most patients become wheelchair-bound between 5 and 30 years old. MRI image analysis shows hypomyelinating leukodystrophy. The phenotype is variable (Bernard et al. 2011. PubMed ID: 21855841; Perrier et al. 2020. PubMed ID: 32582862; Harting et al. 2020. PubMed ID: 31940116).  

Pathogenic variants in POLR3A also cause another severe phenotype, Wiedemann-Rautenstrauch syndrome, which is characterized by growth retardation, sparse scalp hair, generalized lipodystrophy with characteristic local fatty tissue accumulations, and an unusual face. Onset is in utero and death can occur in early childhood (Paolacci et al. 2018. PubMed ID: 30323018).

As hypomyelinating leukodystrophy can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

Genetics

POLR3A-related hypomyelinating leukodystrophy is inherited in an autosomal recessive manner. Pathogenic variants in POLR3A include missense, nonsense, splicing, small deletion/duplications, and small indel variants. Large deletions have also been reported in the POLR3A locus (Human Gene Mutation Database). De novo pathogenic variants are not common.

It has been speculated that genotypes with bi-allelic missense variants or a missense variant in trans with a splicing or truncating variant are causative for the distinct phenotype of hypomyelinating leukodystrophy, whereas bi-allelic splicing or truncating variants, or a strong spicing or truncating variant in trans with a milder hypomorphic variant (often a deep intronic variant partially affecting splicing), are associated with Wiedemann-Rautenstrauch syndrome (Wambach et al. 2018. PubMed ID: 30414627; Paolacci et al. 2018. PubMed ID: 30323018).

POLR3A encodes the largest subunit A of RNA polymerase III, which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs (Bernard et al. 2011. PubMed ID: 21855841; Wambach et al. 2018. PubMed ID: 30414627). However, a mouse model with the French Canadian founder mutation (homozygous Polr3a c.2015G > A (p.Gly672Glu)) did not show neurological abnormalities (Choquet et al. 2017. PubMed ID: 28407788). POLR3A has been cited as an essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in POLR3A are considered one of the major causes of hypomyelinating leukodystrophies. In 37 patients with hypomyelinating leukodystrophies, all had pathogenic variants either in POLR3A (27 cases) or in POLR3B (10 cases; Daoud et al. 2013. PubMed ID: 23355746, Bernard et al. 2011. PubMed ID: 21855841, Tétreault et al. 2011. PubMed ID: 22036172, Potic et al. 2012. PubMed ID: 22451160).

Testing Strategy

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

This test provides full coverage of all coding exons of the POLR3A gene 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 full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

POLR3A sequencing is recommended for patients who are suspected to have hypomyelinating leukodystrophy. Targeted testing is indicated for family members of patients who have known pathogenic variants in POLR3A. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in POLR3A.

Gene

Official Gene Symbol OMIM ID
POLR3A 614258
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bernard et al. 2011. PubMed ID: 21855841
  • Choquet et al. 2017. PubMed ID: 28407788
  • Daoud et al. 2013. PubMed ID: 23355746
  • Harting et al. 2020. PubMed ID: 31940116
  • Human Gene Mutation Database (Biobase).
  • Online Gene Essentiality (OGEE).
  • Paolacci et al. 2018. PubMed ID: 30323018
  • Perrier et al. 2020. PubMed ID: 32582862
  • Potic et al. 2012. PubMed ID: 22451160
  • T├ętreault et al. 2011. PubMed ID: 22036172
  • Wambach et al. 2018. PubMed ID: 30414627

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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