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Perrault Syndrome Type 2 via the HARS2 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
8391 HARS2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8391HARS281479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

Perrault syndrome is a sex-influenced disorder that is characterized by progressive, sensorineural deafness coupled with ovarian dysgenesis or premature ovarian failure (streak gonads), amenorrhea, and infertility in females. This syndrome often goes undetected until puberty or during child-bearing years (Pierce et al. 2011). Perrault syndrome also affects males and is mainly characterized by progressive hearing loss. Affected females are karyotypically 46,XX and infertile; affected males are 46,XY and fertile. Some patients diagnosed with Perrault syndrome also develop neurologic abnormalities, which include mild mental retardation, cerebellar ataxia, and disruptions involving the peripheral nervous system (Huyghe et al. 2006). Due to the clinical heterogeneity of this deafness syndrome, Perrault syndrome has been further classified into two types. Type I is described as static and does not present with neurologic disease, whereas type II is characterized by progressive neurologic disease.

Diagnosing Perrault syndrome in a male patient can be very challenging, especially in the absence of a sister that presents specific symptoms of the syndrome. The average age at diagnosis of Perrault syndrome in females is 22 years old, which is often ascertained by a delay in puberty and the development of sensorineural deafness. Hearing loss in Perrault syndrome is always bilateral, although the severity can be variable (ranging from mild to profound deafness). Ovarian dysgenesis occurs in all female Perrault syndrome patients and is often validated by amenorrhea; however, males do not show any gonadal defects. Approximately 50% of patients with Perrault syndrome show delayed growth, with height often below the third percentile.

Genetics

Perrault syndrome follows an autosomal recessive pattern of inheritance and is caused by variants in the HARS2 gene, also known as PRLTS2, which has been localized to chromosomal band 5q31.3. The HARS2 gene encodes an enzyme called mitochondrial histidine-tRNA ligase, also known as histidine translase and histidyl-tRNA synthetase, which is involved in protein biosynthesis (Olsen et al. 2006). Histidyl-tRNA synthetase is responsible for ligating amino acids onto cognate tRNA molecules (Vester et al. 2013). There are approximately 20 tRNA synthetases that are grouped into two classes based on their primary structure and crystallographic features (Raben et al. 1992; Li et al. 2011). Aside from its involvement with Perrault syndrome, histidyl-tRNA synthetase is also recognized as a common target of autoantibodies in human autoimmune diseases such as polymyositis and dermatomyositism (Ascherman et al. 2002). Other frequent targets of autoantibodies include threonyl-, alanyl-, glycyl-, and isoleucyl-tRNA (Ge et al. 1994).

The HARS2 gene consists of 13 exons and is approximately 6.9 kb. The first two exons of the HARS2 gene encode for a 32-amino acid helical motif that has been conserved from prokaryotes to humans (Raebn et al. 1994). Other genes implicated in the development of Perrault syndrome include CLPP, HSD17B4, PRLTS2, PRLTS3, PRLTS4, and LARS2 (Jenkinson et al. 2013). Most cases of Perrault syndrome are simultaneously reported in at least two female members of a family. In cases where two brothers are involved, these individuals often present a relatively mild phenotype. The causative mutations in the HARS2 gene are mainly missense substitutions (Pierce et al. 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

In a study involving an 11-member nonconsanguineous family, all five affected siblings were compound heterozygotes for variants in the HARS2 gene (Pierce et al. 2011). The paternal allele c.598C>G led to an alternative splice that yielded two transcripts, HARS2 p.L200V and HARS2 p.200-211, whereas the maternal allele c.1102G>T encoded one transcript, HARS2 p.V368L. The affected family members therefore produced three HARS2 transcripts. In ten other families with Perrault syndrome, no HARS2 variants were detected, thus indicating a 17% detection rate in families with Perrault syndrome. The analytical sensitivity of bi-directional sequencing is high because all HARS2 causative mutations reported to date are detectable by this method.

Testing Strategy

This test provides full coverage of all coding exons of the HARS2 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

Females presenting with hearing loss and ovarian failure or infertility, as well as males diagnosed with hearing loss can be offered the HARS2 gene test. The individual should have completed otologic and audiologic tests, as well as ancillary testing such as CT imaging of the inner ear to determine the characteristic abnormality involving the temporal bone (Kumar et al. 2003; Altay et al. 2008). Audioprofiling may also assist in determining the rate of progressive hearing loss each year. Cascade testing or successive testing of family members to trace the inheritance pattern of the identified mutation may be offered. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in HARS2.

Gene

Official Gene Symbol OMIM ID
HARS2 600783
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Perrault Syndrome 2 AR 614926

Citations

  • Altay H, Savas R, Ogüt F, Kirazli T, Alper H. 2008. CT and MRI findings in X-linked progressive deafness.  Diagn Interv Radiol 14: 117–119. PubMed ID: 18814129
  • Ascherman DP, Oriss TB, Oddis CV, Wright TM. 2002. Critical Requirement for Professional APCs in Eliciting T Cell Responses to Novel Fragments of Histidyl-tRNA Synthetase (Jo-1) in Jo-1 Antibody-Positive Polymyositis. The Journal of Immunology 169: 7127–7134. PubMed ID: 12471150
  • Ge Q, Trieu EP, Targoff IN. 1994. Primary structure and functional expression of human Glycyl-tRNA synthetase, an autoantigen in myositis. J. Biol. Chem. 269: 28790–28797. PubMed ID: 7961834
  • Huyghe S, Schmalbruch H, Hulshagen L, Veldhoven PV, Baes M, Hartmann D. 2006. Peroxisomal Multifunctional Protein-2 Deficiency Causes Motor Deficits and Glial Lesions in the Adult Central Nervous System. The American Journal of Pathology 168: 1321–1334. PubMed ID: 16565505
  • Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B, Billington N, Schultz JM, Urquhart JE, Lee MK, Berry A, Hanley NA, Mehta S, Cilliers D, Clayton PE, Kingston H, Smith MJ, Warner TT; University of Washington Center for Mendelian Genomics, Black GC, Trump D, Davis JR, Ahmad W, Leal SM, Riazuddin S, King MC, Friedman TB, Newman WG. 2013. Perrault Syndrome Is Caused by Recessive Mutations in CLPP, Encoding a Mitochondrial ATP-Dependent Chambered Protease. The American Journal of Human Genetics 92: 605–613. PubMed ID: 23541340
  • Kumar G, Castillo M, Buchman CA. 2003. X-linked stapes gusher: CT findings in one patient. American journal of neuroradiology 24: 1130–1132. PubMed ID: 12812938
  • Li L, Weinreb V, Francklyn C, Carter CW. 2011. Histidyl-tRNA synthetase urzymes: Class I and II aminoacyl tRNA synthetase urzymes have comparable catalytic activities for cognate amino acid activation. Journal of Biological Chemistry 286: 10387–10395. PubMed ID: 21270472
  • Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M. 2006. Global, In Vivo, and Site-Specific Phosphorylation Dynamics in Signaling Networks. Cell 127: 635–648. PubMed ID: 17081983
  • Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, Li W, Klevit RE, King M-C. 2011. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proceedings of the National Academy of Sciences 108: 6543–6548. PubMed ID: 21464306
  • Raben N, Borriello F, Amin J, Horwitz R, Fraser D, Plotz P. 1992. Human histidyl-tRNA synthetase: recognition of amino acid signature regions in class 2a aminoacyl-tRNA synthetases. Nucleic acids research 20: 1075–1081. PubMed ID: 1549469
  • Vester A, Velez-Ruiz G, McLaughlin HM, NISC Comparative Sequencing Program, Lupski JR, Talbot K, Vance JM, Züchner S, Roda RH, Fischbeck KH, Biesecker LG, Nicholson G, et al. 2013. A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase ( HARS ) Gene is Neurotoxic In Vivo. Human Mutation 34: 191–199. PubMed ID: 22930593

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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