Perrault Syndrome Type 3 and Deafness, Autosomal Recessive 8 (DFNB8) via the CLPP 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
8691 CLPP 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8691CLPP81479 81479(x2) $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

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. 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; however, it is often underdiagnosed because hypogonadism is not always observed in male patients. 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 1 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. Male patients with Perrault syndrome may present with cerebellar ataxia combined with peripheral neuropathy, as well as azoospermia (Lieber et al. 2014).

Genetics

Perrault syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic sequence variants in the caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) gene, also known as PRLTS3, which has been localized to chromosomal band 19p13.3 (Bross et al. 1995; Santagata et al. 1999). The CLPP gene encodes an endopeptidase that serves as a component of a mitochondrial ATP-dependent proteolytic complex that is involved in the stress signaling pathway (Kang et al. 2002). The CLPP protein is a stable heptamer without proteolytic activity, with a molecular weight of 169.2 kDa; however, in the presence of ATP, this heptamer changes in conformation and undergoes activation of its catalytic site (Kang et al. 2005). The CLPP gene consists of 6 exons and covers approximately 32 kb. Other genes implicated in the development of Perrault syndrome include HSD17B4 (PRLTS1), HARS2 (PRLTS2), and LARS2 (PRLTS4).

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, possibly because only one of the two major domains of the enzyme is affected (either the dehydrogenase or the hydratase domain). Only 3 causative mutations in the CLPP gene have been reported to date, which include two missense mutations and one splicing sequence variant (Jenkinson et al. 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

In a study involving three families consisting of a total of 14 family members (10 affected and 4 unaffected), pathogenic sequence variants were detected in all family members with Perrault syndrome type 3 (Jenkinson et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the CLPP 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 CLPP 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 CLPP.

Gene

Official Gene Symbol OMIM ID
CLPP 601119
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Perrault Syndrome 3 AR 614129

Related Test

Name
Premature Ovarian Failure (POF) Panel

Citations

  • Altay H, Savas R, Ogüt F, Kirazli T, Alper H. 2008. CT and MRI findings in X-linked progressive deafness. Diagnostic and Interventional Radiology. 14: 117–119. PubMed ID: 18814129
  • Bross P, Andresen BS, Knudsen I, Kruse TA, Gregersen N. 1999. Human ClpP protease: cDNA sequence, tissue-specific expression and chromosomal assignment of the gene. FEBS Letters 377(2): 249-252. PubMed ID: 8543061
  • 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. American Journal of Human Genetics 92(4): 605-613. PubMed ID: 23541340
  • Kang SG, Dimitrova MN, Ortega J, Ginsburg A, Maurizi MR. 2005. Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX. Journal of Biological Chemistry 280(42): 35424-35432. PubMed ID: 16115876
  • Kang SG, Ortega J, Singh SK, Wang N, Huang NN, Steven AC, Maurizi MR. 2002. Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP. Journal of Biological Chemistry 277(23): 21095-21102. PubMed ID: 11923310
  • 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
  • Lieber DS, Hershman SG, Slate NG, Calvo SE, Sims KB, Schmahmann JD, Mootha VK. 2014. Next generation sequencing with copy-number-variant detection expands the phenotypic spectrum of HSD17B4-deficiency. BMC medical genetics 15: 30. PubMed ID: 24602372
  • 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
  • Santagata S, Bhattacharyya D, Wang FH, Singha N, Hodtsev A, Spanopoulou E. 1999. Molecular cloning and characterization of a mouse homolog of bacterial ClpX, a novel mammalian class II member of the Hsp100/Clp chaperone family. Journal of Biological Chemistry 274(23): 16311-16319. PubMed ID: 10347188

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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