Perrault Syndrome Type 2 via the HARS2 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1547 HARS2$780.00 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 18 days.

Clinical Sensitivity

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.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 HARS2$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

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.


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).

Testing Strategy

Full gene Sanger sequencing of all coding exons of the HARS2 gene is performed. The full coding region of each exon plus ~20 bp of flanking non-coding DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

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.


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


Name Inheritance OMIM ID
Perrault Syndrome 2 614926


Genetic Counselors
  • 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all 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 for example 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 and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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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.
  • 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.


(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.


(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.


(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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