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Perrault Syndrome Type 1 via the HSD17B4 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4645 HSD17B4$990.00 81479 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
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 28 days.

Clinical Sensitivity

Variants in the HSD17B4 gene have been reported in three out of 6 families with Perrault syndrome (Pierce et al. 2010; Pierce et al. 2011; Pierce et al. 2013; MacMillan et al. 2012; Lines et al. 2014). The analytical sensitivity of bi-directional sequencing is also high because all HSD17B4 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 HSD17B4$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

In a study involving 110 patients with D-BP deficiency, only two patients were determined to have gross deletions, whereas the majority of the detected variants were missense mutations (Ferdinandusse et al. 2006).

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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 age (Pierce et al. 2010). 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 could 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 variants in the HSD17B4 gene, also known as PRLTS1, which has been localized to chromosomal band 5q23.1. The HSD17B4 gene encodes an enzyme called 17-beta-estradiol dehydrogenase, also known as D-bifunctional protein (D-BP), multifunctional enzyme type 2 (MFE-2), and multifunctional protein-2 (MFP-2), which is involved in the beta-oxidation of fatty acids in peroxisomes (Ferdinandusse et al. 2006; Huyghe et al. 2006; Mehtala et al. 2013). The HSD17B4 gene consists of 24 exons and covers approximately 100 kb. Other genes implicated in the development of Perrault syndrome include CLPP (PRLTS3), HARS2 (PRLTS2), and LARS2 (PRLTS4).

The enzyme 17-beta-estradiol dehydrogenase is mainly found in the liver, kidney, ovaries, and testes (De Launoit and Adamski 1999; Huyghe et al. 2006). The HSD17B4 gene is generally stimulated by progesterone, as well as ligands of the peroxisomal proliferator-activated receptor alpha (PPARalpha), including clofibrate. Phorbol esters inhibit the expression of this gene. Mutations in the HSD17B4 gene are also known to cause Zellweger syndrome and peroxisomal D-bifunctional protein deficiency, which also present with hearing impairment (De Launoit and Adamski 1999; Lines et al. 2014)

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). A total of about 80 causative mutations in the HSD17B4 gene have been reported, which include missense mutations, deletions, insertions, and duplications (Pierce et al. 2010). 

Recessive mutations in the HSD17B4 gene also cause D-BP deficiency.  D-BP deficiency is commonly fatal in early childhood, a small number of patients survive beyond 8 years of age (Van Grunsven et al. 1999; McMillan et al. 2012).

Testing Strategy

For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

Indications for Test

Individuals with bilateral sensorineural hearing loss with early-childhood onset can be offered the HSD17B4 test. There should also be no evidence of impaired vestibular function, as indicated by computed tomography (CT) imaging (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 when the patient has been identified as the index case or proband.

Gene

Official Gene Symbol OMIM ID
HSD17B4 601860
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Perrault Syndrome 233400

Related Tests

Name
Peroxisomal Disorders Sequencing Panel
Perrault Syndrome Type 2 via the HARS2 Gene
Perrault Syndrome Type 3 and Deafness, Autosomal Recessive 8 (DFNB8) via the CLPP Gene
Perrault Syndrome Type 4 via the LARS2 Gene

CONTACTS

Genetic Counselors
Geneticist
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
  • de Launoit Y de, Adamski J. 1999. Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome. J. Mol. Endocrinol. 22: 227–240. PubMed ID: 10343282
  • Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T. 2006. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. The American Journal of Human Genetics 78: 112–124. PubMed ID: 16385454
  • 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
  • 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
  • Lines MA, Jobling R, Brady L, Marshall CR, Scherer SW, Rodriguez AR, Lee L, Lang AE, Mestre TA, Wanders RJ, Ferdinandusse S, Tarnopolsky MA; Canadian Pediatric Genetic Disorders Sequencing Consortium (FORGE Canada). 2014. Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing. Neurology 82: 963-968. PubMed ID: 24553428
  • McMillan HJ, Worthylake T, Schwartzentruber J, Gottlieb CC, Lawrence SE, MacKenzie A, Beaulieu CL, Mooyer PA, Wanders RJ, Majewski J, Bulman DE, Geraghty MT, Ferdinandusse S, Boycott KM. 2012. Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J Rare Dis 7: 90. PubMed ID: 23181892
  • Mehtälä ML, Lensink MF, Pietikäinen LP, Hiltunen JK, Glumoff T. 2013. On the Molecular Basis of D-Bifunctional Protein Deficiency Type III. PLoS ONE 8: e53688. PubMed ID: 23308274
  • 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
  • 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
  • Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King M-C. 2010. Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome. The American Journal of Human Genetics 87: 282–288. PubMed ID: 20673864
  • Van Grunsven EG, Mooijer PA, Aubourg P, Wanders RJ. 1999. Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency. Hum. Mol. Genet. 8: 1509–1516. PubMed ID: 10400999
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TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most 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 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.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

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.

Order Kits

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.
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.

SPECIMEN TYPES
WHOLE BLOOD

(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.

DNA

(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.

CELL CULTURE

(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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