1. NGS panel - Genetic testing for arthrogryposis

Arthrogryposis

June 29, 2018

Disease summary

Arthrogryposis refers to multiple congenital joint contractures and resulting restriction of movements. It is a clinical feature that occurs as part of >300 different disorders. Distal arthrogryposes are a specific type of arthrogryposis disorders that involve contractures in ≥2 distal parts of the limbs and the absence of neurological/muscle disease. Pathogenic variants in >10 genes (TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN) that encode proteins important for the myofibers contractile functions, can cause distal arthrogryposis. 1, 2

 


Autosomal dominant

Major clinical symptoms for arthrogryposis include the following 1, 2:

  • Upper limbs:

    • camptodactyly (permanent banding of one or more fingers)
    • hypoplastic and/or absent flexion creases
    • overriding fingers
    • ulnar deviation at the wrist

  • Lower limbs:

    • talipes equinovarus (clubfoot)
    • vertical talus (rocker bottom feet)
    • other foot deformities (calcaneovalgus  talipes, metatarsus varus)

  • ≥2 above major symptoms in an individual
  • ≥1 of the major symptoms in an individual with an affected family member (with ≥2 symptoms)
  • Known pathogenic variant in one of the following genes: TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN

There is no cure for arthrogryposis but different management and interventions can relieve symptoms 1, 2

  • Surgical correction of the contractures
  • Complex multi-disciplinary treatment involving pediatricians, physiotherapists, geneticists, orthopedic surgeons, and orthotic specialists. 
  • Osteochondrodysplasias
  • Holt-Oram syndrome
  • Tuberous sclerosis
  • Otopalatodigital syndrome
  • Nemaline myopathy
  • Oculodentodigital syndrome
  • Ophthalmomandibulomelic dysplasia

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • Arthrogryposis NGS Panel Plus which includes sequencing of the genes TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN
  • Arthrogryposis NGS Panel Plus + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of distal arthrogryposis.
  • Individuals that meet the diagnostic criteria for distal arthrogryposis (regardless of family history).

Why is this test good for the patient?

Confirmation of a clinical diagnosis through genetic testing of Arthrogryposis can allow for genetic counseling and may direct medical management.


Table 1. Overview of genes included in Arthrogryposis panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
DOK7 610285 ?Fetal akinesia deformation sequence; Myasthenic syndrome, congenital, 10 AR 32
ECEL1 605896 Arthrogryposis, distal, type 5D AR 17
FBN2 612570 Contractural arachnodactyly, congenital; Macular degeneration, early-onset AD 46
MYBPC1 160794 Arthrogryposis, distal, type 1B; Lethal congenital contracture syndrome 4 AD, AR 47
MYH3 160720 Arthrogryposis, distal, type 8; Arthrogryposis, distal, type 2A; Arthrogryposis, distal, type 2B AD 54
MYH8 160741 Trismus-pseudocamptodactyly syndrome; Carney complex variant AD 23
PIEZO2 613629 Arthrogryposis, distal, type 5; Arthrogryposis, distal, type 3; ?Marden-Walker syndrome; Arthrogryposis, distal, with impaired proprioception and touch AD, AR 46
RAPSN 601592 Fetal akinesia deformation sequence; Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency AR 12
TNNI2 191043 Arthrogryposis multiplex congenita, distal, type 2B AD 8
TNNT3 600692 Arthrogryposis, distal, type 2B AD 20
TPM2 190990 Arthrogryposis multiplex congenita, distal, type 1; Arthrogryposis, distal, type 2B; CAP myopathy 2; Nemaline myopathy 4, autosomal dominant AD 14

Abbreviations for Table 1: DA-Distal arthrogryposis, FSS-Freeman Sheldon syndrome; SHS-Sheldon-Hall syndrome; FADS-Fetal akinesia syndrome; CMS-Congenital myoasthenic syndrome.

There is no definitive treatment for arthrogryposis, however proper management can prolong survival and improve the quality of life. Physical therapy and prevention of disease-induced complications is of great benefit for patients.