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Lethal Congenital Contracture Syndrome via the ERBB3 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
15441 ERBB3 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15441ERBB381479 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.


Genetic Counselors


  • 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 2 was first described in two consanguineous families (Narkis et al. 2007. PubMed ID: 17701904). Clinical features can include micrognathia, high myopia, respiratory insufficiency, cystic kidneys, hydronephrosis, distended urinary bladder, arthrogryposis, neurogenic muscle atrophy, decreased fetal movement, and polyhydramnios. All affected individuals in both kindreds were homozygous for an intronic variant that alters splicing. An additional study identified another patient with dysmorphic features, knee dislocation, and bilateral hip dislocation who was also homozygous for a missense variant (Alfares et al. 2017. PubMed ID: 28454995). ERBB3 compound heterozygous variants were also reported in an individual with a multi-system disorder including developmental delay, growth retardation, facial malformations, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage (Li et al. 2019. PubMed ID: 31752936). This patient did not present with congenital contractures. Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.


Pathogenic variants in the ERBB3 gene are associated with autosomal recessive lethal congenital contracture syndrome 2 (LCCS2) and possibly other variable phenotypes. Reported variants include missense, splice, and one small duplication that results in a frameshift (Narkis et al. 2007. PubMed ID: 17701904; Alfares et al. 2017. PubMed ID: 28454995; Li et al. 2019. PubMed ID: 31752936). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported. 

The ERRB3 gene encodes an epidermal growth factor (EGF) receptor and is one of four transmembrane glycoprotein EGF receptor tyrosine kinases. Members of this family play a key role in regulation of mammalian cell survival, proliferation, adhesion, and differentiation. Erbb3-/- mice are embryonic lethal at day E11.5-13.5 and show severe anomalies in brain development and abnormal development of the stomach, pancreas, and adrenal glands (Li et al. 2019. PubMed ID: 31752936; Erickson et al. 1997. PubMed ID: 9362461; Riethmacher et al. 1997. PubMed ID: 9338783). However, ERRB3 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 (Narkis et al. 2007. PubMed ID: 17701904; Alfares et al. 2017. PubMed ID: 28454995; Li et al. 2019. PubMed ID: 31752936). 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 ERBB3 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 known pathogenic variants in ERBB3. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ERBB3.


Official Gene Symbol OMIM ID
ERBB3 190151
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Lethal Congenital Contracture Syndrome 2 AR 607598


  • Alfares et al. 2017. PubMed ID: 28454995
  • Beecroft et al. 2018. PubMed ID: 29959180
  • Erickson et al. 1997. PubMed ID: 9362461
  • Li et al. 2019. PubMed ID: 31752936
  • Narkis et al. 2007. PubMed ID: 17701904
  • Online Gene Essentiality (OGEE).
  • Pergande et al. 2020. PubMed ID: 31680123
  • Riethmacher et al. 1997. PubMed ID: 9338783


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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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