Distal Arthrogryposis Panel

Arthrogryposis multiplex congenita (AMC), or arthrogryposis, is a descriptive term for a group of disorders involving congenital contractures affecting two or more joints in different areas of the body. Arthrogryposis is a consequence of decreased or absent fetal movement (fetal hypokinesia or akinesia). Nongenetic etiologies include fetal crowding, uterine abnormalities, decreased amniotic fluid, and maternal illnesses such as myasthenia gravis or Zika infection. Genetic etiologies account for >50% of cases and include chromosome abnormalities and single gene disorders which affect the central nervous system, muscles, nerves, connective tissue, etc.  This group of disorders exhibits both clinical and genetic heterogeneity, making classification and diagnosis difficult, especially in prenatal cases with only approximately 25% of prenatal arthrogryposis diagnosed by ultrasound prior to 24 weeks gestation. 

Disease Overview

Distal arthrogryposes (DAs) are a subset of genetic AMCs that involve contractures of the distal parts of the limbs. The contractures are congenital but occur in the absence of primary neurologic and/or muscle disease. The shared findings among DA include a consistent pattern of hand and foot involvement, limited involvement of the proximal joints, and variable expressivity. There are multiple types of DA caused by different genes (genetic heterogeneity). 

Symptoms of Arthrogryposis

• Multiple congenital contractures
• Decreased fetal movement/akinesia
• Abnormal position of hands/feet
• Central nervous system (CNS) anomalies
• Developmental delay/intellectual disability
• Seizures

Prevalence

Approximately 1/3,000 births 

Genes

ECEL1, FBN2, MYBPC1, MYH3, MYH8,^a NALCN,^a PIEZO2,^a TNNI2, TNNT3, TPM2

^aOne or more exons are not covered by sequencing for the indicated gene (see Limitations).

Inheritance

Variable: dependent on condition (see Genes Tested table)

Test Interpretation

Clinical Sensitivity

Variable: dependent on phenotype/condition

Analytical Sensitivity

For massively parallel sequencing:

Results

Limitations

• A negative result does not exclude a heritable form of arthrogryposis.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
  • Regulatory region and deep intronic variants
  • Large deletions/duplications in any of the tested genes
  • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • MYH8 (NM_002472) exon 5
    • NALCN (NM_001350748) exon 19
    • PIEZO2 (NM_022068) exon 4
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants

Genes Tested