Ehlers-Danlos Syndrome with Progressive Kyphosis, Myopathy, and Hearing Loss (EDSKMH) via the FKBP14 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8865 FKBP14 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8865FKBP1481479 81479(x2) $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

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

Ehlers-Danlos syndrome (EDS) pertains to a clinically and genetically heterogeneous group of heritable connective tissue disorders that mainly affect the skin, joints, ligaments, blood vessels, and internal organs (Byers and Murray 2012). The clinical hallmarks of EDS include skin hyperelasticity, joint hypermobility, and pronounced tissue fragility. One of the six major types of EDS, Ehlers-Danlos syndrome with kyphoscoliosis or EDS type VIA (OMIM 225400), is characterized by severe congenital muscle hypotonia, progressive kyphoscoliosis, extensive skin hyperelasticity with widened atrophic scars, and joint hypermobility. Other common features include osteopenia without a tendency to fractures, a Marfanoid habitus, microcornea, as well as occasional rupture of the arteries and the eye globe. The features of severe muscle hypotonia and delayed motor development in children often lead to a misdiagnosis of EDS VIA as a primary neuromuscular disease. A neuromuscular workup during the neonatal period generally yields normal results. Muscle weakness and fatigability are common symptoms of EDS, which are mainly due to increased distensibility of tendons, a decline in mechanical efficiency due to inadequate intramuscular connective tissue, and avoidance of exercise because of joint instability and/or weak connective tissue surrounding the muscle spindles (Castori and Voermans 2014). Recent studies have shown that the neuromuscular symptoms of EDS may be partly attributable to mild to moderate myopathic and/or neuropathic alterations caused by changes in composition of the extracellular matrix in muscles and peripheral nerves (Byers and Murray 2014).

One rare variant of EDS VIA is Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKMH; OMIM 614557), which presents with the common features of EDS VIA, but with the additional characteristic of sensorineural hearing loss (Baumann et al. 2012). Patients with EDSKMH present with myopathy as determined by clinical, electrophysiological, imaging, as well as muscle biopsy testing.

Genetics

EDSKMH is an autosomal recessive connective tissue disorder that is caused by pathogenic sequence variants in the FK506-binding protein 14 (FKBP14) gene, which encodes for a 22 kDa peptidyl-prolyl cis-trans isomerase (PPIase) that is mainly located in the endoplasmic reticulum (ER) (Baumann et al. 2012). Cis-trans isomerization involving peptidyl-prolyl bonds has been determined to be the rate-limiting step of protein folding, particularly for procollagens, which are largely influenced by the availability of prolyl-residues. The process of protein folding is accelerated by the action of PPIases, which serve as folding catalysts, as well as act as molecular chaperones. In silico analysis has indicated that the putative FKBP14 protein possesses a PPIase FKBP-type domain that comprises two elongation factor (EF)-hand motifs and one retention signal (Boudko et al. 2014). Pathogenic sequence variants in the FKBP14 gene result in FKBP14 deficiency, which in turn causes enlargement of ER cisterns as well as disarray of the extracellular matrix (Baumann et al. 2012).

To date, only two studies have been conducted on EDSKMH via the FKBP14 gene, describing two pathogenic small deletions and one small insertion. In one study, five patients from four families with EDSKMH were determined to be homozygous for a 1-bp insertion within exon 3 (c.362dupC), resulting in a frameshift that is predicted to generate a premature termination codon (p.Glu122Argfs*7) (Baumann et al. 2012). Further examination of another unrelated patient with EDSKMH showed compound heterozygosity for the same 1-bp insertion and a 19-bp deletion (c.42_60del19) that leads to a premature stop codon (p.Thr15*). Electron microscopy and immunofluorescence studies of fibroblasts from these patients showed abnormal distribution and organization of the extracellular matrix, including types I and III collagens, as well as fibronectin. In another study, a three-year-old boy with EDSKMH was determined to be homozygous for a 4-bp deletion (c.197+5_197+8delGTAA) affecting splicing (Aldeeri et al. 2014).

Clinical Sensitivity - Sequencing with CNV PG-Select

Because only two reports (Baumann et al. 2012; Aldeeri et al. 2014) have described three pathogenic sequence variants in a total of seven patients, it is difficult to estimate the clinical sensitivity of this test. Analytical sensitivity should be high because all mutations reported are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the FKBP14 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients that have been diagnosed with EDSKMH. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in FKBP14.

Gene

Official Gene Symbol OMIM ID
FKBP14 614505
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Aldeeri AA, Alazami AM, Hijazi H, Alzahrani F, Alkuraya FS. 2014. Excessively redundant umbilical skin as a potential early clinical feature of Morquio syndrome and FKBP14-related Ehlers-Danlos syndrome. Clinical Genetics 86(5): 469-472. PubMed ID: 24773188
  • Baumann M, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, Schreiber G, Zou Y, Hu Y, Romero NB, Carlier RY, Amberger A, Deutschmann A, Straub V, Rohrbach M, Steinmann B, Rostásy K, Karall D, Bönnemann CG, Zschocke J, Fauth C. 2012. Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. American Journal of Human Genetics 90(2): 201-216. PubMed ID: 22265013
  • Baumann M1, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, Schreiber G, Zou Y, Hu Y, Romero NB, Carlier RY, Amberger A, Deutschmann A, Straub V, Rohrbach M, Steinmann B, Rostásy K, Karall D, Bönnemann CG, Zschocke J, Fauth C. 2012. Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. American Journal of Human Genetics 90(2): 201-216.
  • Boudko SP, Ishikawa Y, Nix J, Chapman MS, Bächinger HP. 2014. Structure of human peptidyl-prolyl cis-trans isomerase FKBP22 containing two EF-hand motifs. Protein Science 23(1): 67-75. PubMed ID: 24272907
  • Byers PH, Murray ML. 2012. Heritable collagen disorders: the paradigm of the Ehlers-Danlos syndrome. Journal of Investigative Dermatology 132(E1): E6-11. PubMed ID: 23154631
  • Byers PH, Murray ML. 2014. Ehlers-Danlos syndrome: A showcase of conditions that lead to understanding matrix biology. Matrix Biology 33: 10-15. PubMed ID: 23920413
  • Castori M, Voermans NC. 2014. Neurological manifestations of Ehlers-Danlos syndrome(s): A review. Iran Journal of Neurology 13(4): 190-208. PubMed ID: 25632331

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

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


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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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