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Lethal Congenital Contracture Syndrome 9 via the ADGRG6 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
15443 ADGRG6 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15443ADGRG681479 81479,81479 $990 Order Options and Pricing

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 platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Fetal akinesia (FA) describes a clinical syndromic entity characterized by reduced or absent fetal movements resulting in multiple phenotypic abnormalities. These secondary defects may include intrauterine growth restriction (IUGR), craniofacial dysmorphic features (cleft palate or retromicrognathia), limb pterygia, pulmonary hypoplasia, and arthrogryposis. This group of disorders contains several overlapping conditions ranging from distal arthrogryposis, multiple pterygium syndrome, and arthrogryposis multiplex congenita (AMC) to the more severe lethal congenital contracture syndrome and fetal akinesia deformation sequence (FADS; Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

AMC is defined by congenital, non-progressive contractures in more than two joints and in multiple body areas. These contractures and reduced fetal movement can lead to secondary polyhydramnios or fetal hydrops. The underlying defect can be genetic or environmental. Causes can include muscle disorders, neurological disorders, connective tissue disorders, fetal vascular compromise, uterine space limitations, and maternal disease or drug use. The overall incidence of AMC ranges from 1/3,000 to 1/5,000 live births (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

Lethal congenital contracture syndrome 9 (LCCS9) was first described in three consanguineous families (Ravenscroft et al. 2015. PubMed ID: 26004201). All affected individuals were homozygous for missense, nonsense, or frameshift variants. Clinical features can include intrauterine growth retardation; micrognathia; dysmorphic features; pulmonary hypoplasia; contractures of wrists, elbows, and fingers; talipes equinovarus; decreased fetal movements; and polyhydramnios. Onset is in utero and fetal anomalies are typically observed on prenatal ultrasound. Respiratory failure typically results in death soon after birth. Additional compound heterozygous or homozygous patients with ADGRG6 variants and features of LCCS9 have been reported in several additional families (Daum et al. 2019. PubMed ID: 29947050; Vora et al. 2020. PubMed ID: 31974414; Normand et al. 2018. PubMed ID: 30266093). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Genetics

Pathogenic variants in the ADGRG6 gene (also referred to as GPR126 in the literature) are associated with autosomal recessive lethal congenital contracture syndrome 9 (LCCS9). Reported variants include nonsense, missense, and a small duplication that results in a frameshift (Ravenscroft et al. 2015. PubMed ID: 26004201; Daum et al. 2019. PubMed ID: 29947050; Vora et al. 2020. PubMed ID: 31974414; Normand et al. 2018. PubMed ID: 30266093). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported. 

The ADGRG6 gene encodes adhesion G protein-coupled receptor G6 which is essential for myelination of axons in the peripheral nervous system. ADGRG6 drives the differentiation of promyelinating Schwann cells by elevating cyclic AMP levels (Monk et al. 2009. PubMed ID: 19745155; Glenn and Talbot. 2013. PubMed ID: 23804499). Affected individuals from one family were found to lack myelin basic protein, providing evidence that ADGRG6 is critical for myelination of the peripheral nerves. Gpr126-null mice have abnormal joint contractures of the limbs by P4 (Ravenscroft et al. 2015. PubMed ID: 26004201; Monk et al. 2011. PubMed ID: 21613327). The ADGRG6 gene (listed as GPR126 in the study) is not considered an essential gene in the human genome (CS = 0.254 in Wang et al. 2015. PubMed ID: 26472758).

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature (Ravenscroft et al. 2015. PubMed ID: 26004201; Daum et al. 2019. PubMed ID: 29947050; Vora et al. 2020. PubMed ID: 31974414; Normand et al. 2018. PubMed ID: 30266093). Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

Testing Strategy

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

This test provides 99.4% coverage of the ADGRG6 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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. Of note, this test does not analyze the 2 nucleotides of exon 1 due to paralogy.

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

Candidates for this test are patients with clinical features consistent with a diagnosis of lethal contracture syndrome or arthrogryposis multiplex congenita. Targeted testing is indicated for family members of patients who have known pathogenic variants in ADGRG6. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ADGRG6.

Gene

Official Gene Symbol OMIM ID
ADGRG6 612243
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Lethal congenital contracture syndrome 9 AR 616503

Citations

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

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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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