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.


Overview of the genes in CENTOGENE´s Arthrogryposis panel:

Gene (OMIM)
Chr.locus
Protein Specific clinical features Associated/allelic disorders (OMIM)
TPM2 (190990)
9p13.3
Tropomiosin 2 Camptodactyly and clubfoot)
Hypoplasia and/or absence of some interphalangeal creases
DA1A (108120); DA2B (601680); NEM4 (609285)
MYBPC1 (160794)
12q23.2
Myosin-binding protein C Clubfoot and congenital vertical talus)
Bilateral lower limb contractures)
Campodactily in some patients
DA1B (614335); LCCS4 (614915)
MYH3 (160720)
17p13.1
Myosin skeletal heavy chain embryonic protein 3 FSS: oropharyngeal abnormalities, scoliosis, and a distinctive face)
SHS: more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth
DA2A/FSS (193700); DA2B/SHS (601680);DA8 (178110)
TNNT3 (600692)
11p15.5
Troponin fast skeletal T3 protein Congenital contractures with craniofacial abnormalities (prominent nasolabial folds, downslanting palpebral fissures, small mouth) DA2B/SHH (601680)
TNNI2 (191043)
11p15.5
Troponin fast-twich skeletal muscle isoform I Congenital contractures with craniofacial abnormalities (prominent nasolabial folds, downslanting palpebral fissures, small mouth) DA2B/SHH (601680)
MYH8 (160741)
17p13.1
Myosin skeletal muscle heavy chain 8 Pseudocamptodactyly of the hands and feet, trismus, in some patients cardiac myxomas DA7 (158300); Carney complex variant (608837)
FBN2 (612570)
5q23.3
Firbillin 2 Contractures, arachnodactyly, scoliosis, and crumpled ears)
Early onset macular degeneration
DA9 (121050); EOMD (616118)
PIEZO2 (613629)
18p11
Piezo-type mechanosensitive ion channel component 2 Congenital contractures with ocular abnormalities (ptosis, restricted extraocular movement, strabismus) DA5 (108145); DA3 (114300); DAIPT (617146); MWKS (248700)
ECEL1 (605896)
2q37.1
Endothelin-converting enzyme like 1 Severe camptodactyly of the hands, mild in toes, clubfoot, unilateral ptosis, characteristic facies DA5D (615065)
DOK7 (610285)
4p16.3
Downstream of tyrosine kinase 7 Fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism FADS (208150); CMS10 (254300)
RAPSN (601592)
11p11.2
Receptor-associated protein of the synapse 43kD Fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism FADS (208150); CMS11 (616326)

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.