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Lethal Congenital Contracture Syndrome 8 via the ADCY6 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
13077 ADCY6 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13077ADCY681479 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, 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 8 was first described in a consanguineous family. Two siblings were found to harbor a homozygous missense variant in ADCY6. Both patients had distal joint contractures, severe hypotonia, lack of swallowing, autonomous respiratory functions and death occurred within the first 3 months of life (Laquérriere et al. 2014. PubMed ID: 24319099). Another patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis was also found to be homozygous for a missense variant in ADCY6 and passed away at 18 months of age. The family history was significant for a deceased sibling with similar features (Gonzaga-Jauregui et al. 2015. PubMed ID: 26257172). A more recent report identified compound heterozygous variants in ADCY6 in a patient with AMC, hypotonia, respiratory failure, areflexia, and severe feeding difficulty. This patient was also found to have a dysmorphic corpus callosum, shunted hydrocephalus, and fatty replacement of muscle tissues on MRI, indicating there is likely a phenotypic spectrum for ADCY6 disorders (Agolini et al. 2020. PubMed ID: 31846058). Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Genetics

Pathogenic variants in the ADCY6 gene are associated with autosomal recessive lethal congenital contracture syndrome 8 (LCCS8). A splice variant and missense variants have been reported in 4 individuals with LCCS8 from 3 families (Laquérriere et al. 2014. PubMed ID: 24319099; Gonzaga-Jauregui et al. 2015. PubMed ID: 26257172; Agolini et al. 2020. PubMed ID: 31846058). The 4 individuals included one individual with compound heterozygous ADCY6 pathogenic variants and two siblings and another unrelated case homozygous for ADCY6 pathogenic variants. To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported. ADCY6 is relatively intolerant to loss of function variants (Genome Aggregation Database).

The ADCY6 gene encodes the adenylyl cyclase type 6, a membrane-associated enzyme that catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). Knockdown of ADCY6 orthologs in zebrafish shows a loss of myelin basic protein expression in the peripheral nervous system (Laquérriere et al. 2014. PubMed ID: 24319099). ADCY6 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

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 (Laquérriere et al. 2014. PubMed ID: 24319099; Gonzaga-Jauregui et al. 2015. PubMed ID: 26257172; Agolini et al. 2020. PubMed ID: 31846058). 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 full coverage of all coding exons of the ADCY6 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 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

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 a known pathogenic variant in ADCY6. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ADCY6.

Gene

Official Gene Symbol OMIM ID
ADCY6 600294
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Lethal congenital contracture syndrome 8 AR 616287

Citations

  • Agolini et al. 2020. PubMed ID: 31846058
  • Beecroft et al. 2018. PubMed ID: 29959180
  • Genome Aggregation Database.
  • Gonzaga-Jauregui et al. 2015. PubMed ID: 26257172
  • Laquérriere et al. 2014. PubMed ID: 24319099
  • Online Gene Essentiality (OGEE).
  • Pergande et al. 2020. PubMed ID: 31680123

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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View Ordering Instructions

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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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