1. NGS panel - Genetic testing for arthrogryposis


July 25, 2017

Clinical features

Arthrogryposis is a clinical feature of joint contractures and resulting restriction of movements and is characteristic for more than 300 different disorders 1, 2. Arthrogryposis, e.g. congenital contractures, can be isolated contractures, affecting only a single area of the body, or multiple. The most common isolated contracture is congenital clubfoot, which occurs in one of every 500 live births 1, 2. The overall prevalence of arthrogryposis is one in 3000 live births 2.

Distal arthrogryposes are a group of autosomal dominant congenital contractures that mainly involve the distal parts of the limbs. Clinical features common for all distal arthrogryposes include a consistent pattern of hand and foot involvement, limited involvement of proximal joints, and variable symptoms expressivity. There are more than 10 different distal arthrogryposes described to date (Table).

Mutations in at least 11 genes (TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN) which encode proteins important for the myofibers contractile functions can cause distal arthrogryposis.

Most typical arthrogryposis is distal arthrogryposis type 1 (DA1), usually characterized by camptodactyly (permanent banding of one or more fingers) and clubfoot (congenital foot deformity “talipes equinovarus”). A common finding is also hypoplasia and/or absence of some interphalangeal creases. The degree to which the joints are affected is highly variable, ranging from mild to severe. With the mildest form of DA1, affected individuals have only hypoplasia of the gastrocnemius. DA1 is caused by heterozygous mutations in the TPM2 gene on chromosome 9p13.

Distal Arthrogryposis Type 1B (DA1B) is characterized with bilateral lower limb contractures, clubfoot, congenital vertical talus and camptodactyly. Mutations in MYBPC1, encoding myosin binding protein, are causative.

Distal Arthrogryposis Type 2 (DA2) is phenotypically similar to DA1. In addition to contractures of the hands and feet, DA2 is characterized by oropharyngeal abnormalities, scoliosis, and characteristic facial features. Patients frequently display a small oral orifice, puckered lips, and an H-shaped dimple of the chin (“whistling-face syndrome”). The disease is caused by mutations in either the MYH3 gene on chromosome 17p13 (DA2A; Freeman-Sheldon syndrome; FSS) or by mutations in the MYH3, TNNT3, TNNI2 or TPM2 genes (DNA2B; Sheldon-Hall syndrome, FSS-variant). Mutations in MYH3 explain approximately 90% of the cases of FSS and approximately 40% of the cases of SHS, making the MYH3 mutation the most common cause of distal arthrogryposis 3, 4.

Distal arthrogryposis type 3 (Gordon syndrome) is distinguished from other distal arthrogryposes by short stature and cleft palate, and it is caused by mutations in the PIEZO2 gene on chromosome 18p11.

Distal arthrogryposis type 4 (DA4) is a subtype of congenital contractures characterized by severe scoliosis. DA4 was previously reported as “distal arthrogryposis type II D” and the chromosomal locus is still unknown.

Distal arthrogryposis type 5 (DA5) is distinguished from other forms of distal arthrogryposis by the presence of ocular abnormalities, such as ptosis, ophthalmoplegia and strabismus, in addition to congenital contractures. Some DA5-affected patients have been reported to have pulmonary hypertension as a result of restrictive lung disease DA5 is caused by mutations in PIEZO2 on chromosome 18p11. Mutations in the same gene are also causing DA3.

The autosomal recessive form of distal arthrogryposis, designated as DA5D, is characterized by severe camptodactyly of the hands, mild camptodactyly of the toes, clubfoot and/or a calcaneovalgus deformity, and characteristic facial features including unilateral ptosis, a round-shaped face; arched eyebrows, bulbous nose, and micrognathia. DA5D is caused by mutations in the ECEL1 gene on chromosome 2q37.1.

Distal arthrogryposis type 6 (DA6) is a form of congenital contractures accompanied by sensorineural deafness. The genetic locus has not yet been identified and the disease is very rare, with only few patients reported so far.

Distal Arthrogryposis Type 7 (DA7), also known as trismus-pseudocamptodactyly syndrome (TPS) is a rare form of distal arthrogryposis characterized by the inability to fully open the mouth (trismus) and pseudocamptodactyly. Some affected patients show shortened hamstring muscles and short stature. DA7 is caused by mutations in MYH8 on chromosome 17p13.1.

Distal Arthrogryposis Type 8 (DA8) is also known as “multiple pterygium syndrome” and is characterized with great phenotypic variability. In addition to congenital contracture of distal muscles, affected patients showed severe scoliosis and ptosis. DA8 is caused by heterozygous mutations in the MYH3 that also cause distal arthrogryposis types 2A (DA2A) and 2B (DA2B).

Distal arthrogryposis type 9 (DA9), also known as Beals syndrome, is a form of distal arthrogryposis characterized with congenital contractural arachnodactyly, scoliosis and crumpled ears. The disease is caused by mutations in the FBN2 gene on chromosome 5q23.3.

Distal arthrogryposis type 10 (DA10) is characterized with congenital plantar contractures and the presence of the congenital short tendo calcaneus. Chromosomal locus is assigned to 2q31.3-q32.1.

Another form of arthrogryposis is fetal akinesia deformation sequence, also known as arthrogryposis multiplex congenital with pulmonary hypoplasia, is characterized with fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism. This form of arthrogryposis is associated with mutations in the genes DOK7 and RAPSN, also known to cause congenital myastenic syndrome.

Overview of genes included in the Arthrogryposis panel offered by CENTOGENE

Gene (OMIM)
Protein Specific clinical features Associated/allelic disorders (OMIM)
TPM2 (190990)
Tropomiosin 2 Camptodactyly and clubfoot)
Hypoplasia and/or absence of some interphalangeal creases
DA1A (108120); DA2B (601680); NEM4 (609285)
MYBPC1 (160794)
Myosin-binding protein C Clubfoot and congenital vertical talus)
Bilateral lower limb contractures)
Campodactily in some patients
DA1B (614335); LCCS4 (614915)
MYH3 (160720)
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)
Troponin fast skeletal T3 protein Congenital contractures with craniofacial abnormalities (prominent nasolabial folds, downslanting palpebral fissures, small mouth) DA2B/SHH (601680)
TNNI2 (191043)
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)
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)
Firbillin 2 Contractures, arachnodactyly, scoliosis, and crumpled ears)
Early onset macular degeneration
DA9 (121050); EOMD (616118)
PIEZO2 (613629)
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)
Endothelin-converting enzyme like 1 Severe camptodactyly of the hands, mild in toes, clubfoot, unilateral ptosis, characteristic facies DA5D (615065)
DOK7 (610285)
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)
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.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the genes in the Arthrogryposis panel (TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1, DOK7, RAPSN).

Differential diagnosis

The differential diagnosis of arthrogryposis disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Osteochondrodysplasias
  • Holt-Oram syndrome
  • Tuberous sclerosis
  • Otopalatodigital syndrome
  • Nemaline myopathy
  • Oculodentodigital syndrome
  • Ophthalmomandibulomelic dysplasia.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for arthrogryposis using NGS Panel Genomic targeted towards this specific cerebellar ataxia phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Arthrogryposis panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Arthrogryposis panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for arthrogryposis testing:

  • Individuals with a family history of arthrogryposis and presentation of the most common symptoms
  • Individuals without a positive family history of arthrogryposis, but with symptoms resembling the disease
  • Individuals with a negative but suspected family history of arthrogryposis, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the arthrogryposis panel genes should be performed in all individuals suspected of having early infantile epileptic encephalopathy and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the arthrogryposis and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Arthrogryposis panel can be found in our genetic test catalogue.