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Perrault Syndrome Type 4 via the LARS2 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
8055 LARS2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8055LARS281479 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) and infertility in females; however, this syndrome often goes undetected until puberty or during child-bearing age (Pierce et al. 2010). 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).

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 several genes, including the LARS2 gene, also known as the LEURS or PRLTS4 gene, which has been localized to chromosomal band 3p21.3 (Pierce et al. 2010, Pierce et al. 2013). However, a recent study involving two families affected by premature ovarian failure and hearing loss has identified three LARS2 variants in five affected children (Pierce et al. 2013).

The LARS2 gene consists of 20 exons and encodes a mitochondrial leucyl-tRNA synthetase 2 protein, also called leucine translase and leucine tRNA ligase, which plays a major role in aminoacylation (Lue et al. 2007; Hsu et al. 2008). The protein is generally expressed as a soluble protein (Ling et al. 2005). Variants in the LARS2 have also been implicated in the etiology of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and type 2 diabetes (Kadowaki et al. 1994; Li et al. 2010; M’t Hart et al. 2005; Reiling et al. 2010; Karicheva et al. 2011). Other genes implicated in the development of Perrault syndrome include CLPP, HSD17B4 and HARS2.

Mitochondrial leucyl-tRNA synthetase 2 is a 903-amino acid polypeptide that is highly expressed in tissues characterized by high metabolic rates, including skeletal muscles, kidney, and heart (Higashikata et al. 2001). Aside from aminoacylation, this protein also facilitates in the association of the mRNA strand to ribosomes, which is an essential step in protein synthesis (Chomyn et al. 2000). This enzyme also assists in the modification of the wobble U base, which is related to the incorporation of the correct amino acid in the growing polypeptide strand (Sasarman et al. 2008).

Most cases of Perrault syndrome are simultaneously reported in at least two female members of a family. In cases wherein two brothers are involved, these individuals often present a relatively mild phenotype. Only a few variants in the LARS2 gene have been reported, which include two missense mutations and one small deletion (Pierce et al. 2013). There is also evidence that the leucyl-tRNA synthetase 2 protein plays an important role in the respiratory chain (King et al. 1992).

Clinical Sensitivity - Sequencing with CNV PGxome

Based on the limited number of reports on LARS2 variants, the clinical sensitivity cannot be determined. The analytical sensitivity of bi-directional sequencing is high because all LARS2 causative mutations reported to date are detectable by this method.

Testing Strategy

This test provides full coverage of all coding exons of the LARS2 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

Individuals presenting with hearing loss and an enlargement of the vestibular aqueduct can be offered the LARS2 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 abnormalities in the temporal bone. 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 when the patient has been identified as the index case or proband. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in LARS2.

Gene

Official Gene Symbol OMIM ID
LARS2 604544
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Perrault Syndrome 4 AR 615300

Citations

  • Chomyn A, Enriquez JA, Micol V, Fernandez-Silva P, Attardi G. 2000. The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated human mitochondrial tRNALeu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes. Journal of Biological Chemistry 275: 19198-19209. PubMed ID: 10858457
  • Higashikata T, Koyama J, Shimada H, Yazaki M, Owa M, Ikeda S. 2001. An 80-year-old mitochondrial disease patient with A3243G tRNA(Leu(UUR)) gene presenting cardiac dysfunction as the main symptom. Internal Medicine 40: 405-408. PubMed ID: 11393411
  • Hsu JL, Martinis SA. 2008. A flexible peptide tether controls accessibility of a unique C-terminal RNA-binding domain in leucyl-tRNA synthetases. Journal of Molecular Biology 376: 482-491. PubMed ID: 18155724
  • 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. American Journal of Pathology 168:1321-1334. PubMed ID: 16565505
  • Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y, Tanabe Y, Sakura H, Awata T, Goto Y, et al. 1994. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. New England Journal of Medicine 330: 962-968. PubMed ID: 8121460
  • Karicheva OZ, Kolesnikova OA, Schirtz T, Vysokikh MY, Mager-Heckel AM, Lombès A, Boucheham A, Krasheninnikov IA, Martin RP, Entelis N, Tarassov I. 2011. Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria. Nucleic Acids Research 39: 8173-8186. PubMed ID: 21724600
  • King MP, Koga Y, Davidson M, Schon EA. 1992. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Molecular and Cellular Biology 12: 480-490. PubMed ID: 1732728
  • Li R, Guan MX. 2010. Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. Molecular and Cellular Biology 30: 2147-2154. PubMed ID: 20194621
  • Ling C, Yao YN, Zheng YG, Wei H, Wang L, Wu XF, Wang ED. 2005. The C-terminal appended domain of human cytosolic leucyl-tRNA synthetase is indispensable in its interaction with arginyl-tRNA synthetase in the multi-tRNA synthetase complex. Journal of Biological Chemistry 280: 34755-34763. PubMed ID: 16055448
  • Lue SW, Kelley SO. 2007. A single residue in leucyl-tRNA synthetase affecting amino acid specificity and tRNA aminoacylation. Biochemistry 46: 4466-4472. PubMed ID: 17378584
  • M't Hart LM, Hansen T, Rietveld I, Dekker JM, Nijpels G, Janssen GM, Arp PA, Uitterlinden AG, Jørgensen T, Borch-Johnsen K, Pols HA, Pedersen O, van Duijn CM, Heine RJ, Maassen JA.2005. Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene. Diabetes 54: 1892-1895. PubMed ID: 15919814
  • Pierce SB , Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC. 2010. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. American Journal of Human Genetics 87: 282-288. PubMed ID: 20673864
  • Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, Klevit RE, King MC, Levy-Lahad E. 2013. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. American Journal of Human Genetics 92: 614-620. PubMed ID: 23541342
  • Reiling E, Jafar-Mohammadi B, van 't Riet E, Weedon MN, van Vliet-Ostaptchouk JV, Hansen T, Saxena R, van Haeften TW, Arp PA, Das S, Nijpels G, Groenewoud MJ, van Hove EC, Uitterlinden AG, Smit JW, Morris AD, Doney AS, Palmer CN, Guiducci C, Hattersley AT, Frayling TM, Pedersen O, Slagboom PE, Altshuler DM, Groop L, Romijn JA, Maassen JA, Hofker MH, Dekker JM, McCarthy MI, 't Hart LM. 2010. Genetic association analysis of LARS2 with type 2 diabetes. Diabetologia 53: 103-110. PubMed ID: 19847392
  • Sasarman F, Antonicka H, Shoubridge EA.2008. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Human Molecular Genetics 17: 3697-3707. PubMed ID: 18753147

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.
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