Klippel-Feil Syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
12621 GDF3 81479,81479 Order Options and Pricing
GDF6 81479,81479
MEOX1 81479,81479
MYO18B 81479,81479
PAX1 81479,81479
RIPPLY2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
12621Genes x (6)81479 81479 $930 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Congenital vertebral malformation (CVM) is a birth defect of the vertebral column with an estimated prevalence of 0.13-0.51 per 1,000 live births (Giampietro et al. 2009. PubMed ID: 19154516). It can be further divided into several groups such as Klippel-Feil syndrome and Spondylocostal Dysostosis. Fetal ultrasound can detect vertebrae defects as early as 13 weeks gestation (Turnpenny et al. 2017. PubMed ID: 20301771).

Patients with Klippel-Feil syndrome (KFS) share the defining characteristic of fused cervical vertebrae. (Tracy et al. 2004. PubMed ID: 15241163). Common clinical features include a short neck, low posterior hairline, restricted range of head movement, and scoliosis (60% of patients). Some scoliosis occurs congenitally. Less common clinical features include rib abnormalities, kidney and heart malformations, deafness, ocular anomalies and respiratory problems (Lewis et al. 2009. hmedscape.com). In one series of patients, the average age at onset of symptoms was 7.1 years, and mean age at onset of cervical spine related symptoms was 11.9 years (Samartzis et al. 2006. PubMed ID: 17023841).

Molecular genetic testing is advantageous to establish an accurate diagnosis for individuals with KFS or related conditions.

Genetics

Pathogenic variants in the GDF6 gene have been reported in patients with both autosomal dominant and recessive KFS (Tracy et al. 2004. PubMed ID: 15241163; Tassabehji et al. 2008. PubMed ID: 18425797; Asai-Coakwell et al. 2009. PubMed ID: 19129173). GDF6 encodes growth differentiation factor 6, a member of the bone morphogenetic protein family. More than 10 missense variants, one splicing, one small truncating variant were reported Human Gene Mutation Database (HGMD). Missense variants in GDF6 have also been reported in a few patients with synostoses syndrome (Terhal. 2018. PubMed ID: 29130651; Wang et al. 2016. PubMed ID: 26643732) and retinal dystrophies (Asai-Coakwell et al. 2013. PubMed ID: 23307924). In addition, two large duplications involving GDF6 and a few other genes were found in two patients with Leri's pleonosteosis (Banka et al. 2015. PubMed ID: 24442880). One large complex arrangement involving the GDF6 gene has been reported in a patient with KFS (Tassabehji et al. 2008. PubMed ID: 18425797).

Several variants in GDF3 (mostly missense) were reported to be associated with autosomal dominant ocular and skeletal anomalies. Some of these variants are probably too common in the healthy population to be a primary cause of disease (Ye et al. 2010. PubMed ID: 19864492; Patel et al. 2018. PubMed ID: 29450879). The GDF3 protein, coded by GDF3, is a member of bone morphogenetic protein family in the transforming growth factor beta (TGFβ) superfamily, which regulates the growth and maturation of bone and cartilage.

MEOX1, coded by MEOX1, is a homeodomain-containing protein that is highly expressed in mesodermally derived embryonic tissues and plays a key role in all somite development (Skuntz et al. 2009. PubMed ID: 19520072). To date, four homozygous causative variants (1 missense, 3 truncating) have been reported in four presumably unrelated consanguineous KFS families (Bayrakli et al. 2013. PubMed ID: 24073994; Mohamed et al. 2013. PubMed ID: 23290072; Lefebvre et al. 2018. PubMed ID: 29459493).

MYO18B is not a well-studied gene. Only a few variants are documented in HGMD, but one homozygous nonsense variant was reported in one consanguineous family with Klippel-Feil anomaly, myopathy, and characteristic facies (Alazami et al. 2015. PubMed ID: 25748484).

The PAX1 protein coded by the PAX1 gene is a member of the paired box family of transcription factors that plays a key role in pattern formation during embryogenesis and development of the vertebral column. Homozygous defects of PAX1 in mice showed mild vertebral defects (Adham et al. 2005. PubMed ID: 16093716). Rare variants in the PAX1 gene have been reported in a few patients with KFS, autosomal recessive otofaciocervical syndrome (McGaughran et al. 2003. PubMed ID: 12774041; Pohl et al. 2013. PubMed ID: 23851939). The inheritance pattern of PAX1 related KFS is not fully defined (McGaughran et al. 2003. PubMed ID: 12774041). The documented PAX1 variants are: missense (5), truncating (3) and splicing (2).

Only two RIPPLY2 truncating variants and one splicing variant were reported in three patients from two families with autosomal recessive vertebral segmentation defects or KFS (Karaca et al. 2015. PubMed ID: 26238661; McInerney-Leo et al. 2015. PubMed ID: 25343988).

De novo pathogenic variants do not seem to be a major contributing factor for KFS as to our knowledge, none have been reported (HGMD).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

Clinical sensitivity is difficult to estimate because only a small number of patients with KFS have been reported. Analytical sensitivity should be high.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

This test is suitable for patients presenting with fused cervical vertebrae or a clinical suspicion of KFS.

Genes

Official Gene Symbol OMIM ID
GDF3 606522
GDF6 601147
MEOX1 600147
MYO18B 607295
PAX1 167411
RIPPLY2 609891
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Adham et al. 2005. PubMed ID: 16093716
  • Alazami et al. 2015. PubMed ID: 25748484
  • Asai-Coakwell et al. 2009. PubMed ID: 19129173
  • Asai-Coakwell et al. 2013. PubMed ID: 23307924
  • Banka et al. 2015. PubMed ID: 24442880
  • Bayrakli et al. 2013. PubMed ID: 24073994
  • Giampietro et al. 2009. PubMed ID: 19154516
  • Human Gene Mutation Database (Biobase).
  • Karaca et al. 2015. PubMed ID: 26238661
  • Lefebvre et al. 2018. PubMed ID: 29459493
  • McGaughran et al. 2003. PubMed ID: 12774041
  • McInerney-Leo et al. 2015. PubMed ID: 25343988
  • Mohamed et al. 2013. PubMed ID: 23290072
  • Patel et al. 2018. PubMed ID: 29450879
  • Pohl et al. 2013. PubMed ID: 23851939
  • Samartzis et al. 2006. PubMed ID: 17023841
  • Skuntz et al. 2009. PubMed ID: 19520072
  • Tassabehji et al. 2008. PubMed ID: 18425797
  • Terhal. 2018. PubMed ID: 29130651
  • Tracy et al. 2004. PubMed ID: 15241163
  • Turnpenny et al. 2017. PubMed ID: 20301771
  • Wang et al. 2016. PubMed ID: 26643732
  • Ye et al. 2010. PubMed ID: 19864492

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.

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 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.

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