Distal Arthrogryposis Panel - Clinical Genetic Test - GTR

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Distal Arthrogryposis Panel

Clinical Genetic Test

offered by

Genetic Services Laboratory

View lab's test page

GTR Test Accession: GTR000506317.5

CAP

INHERITED DISEASEDYSMORPHOLOGYMUSCULOSKELETAL ... View more

Last updated in GTR: 2020-08-11

Last annual review date for the lab: 2023-07-18

At a Glance

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; ...

Conditions (12):

Arthrogryposis, distal, type 1A; Arthrogryposis, distal, type 1B; Arthrogryposis-like hand anomaly-sensorineural deafness syndrome; ...

Genes (11):

CHST14 (15q15.1), ECEL1 (2q37.1), FBN2 (5q23.3), MYBPC1 (12q23.2), MYH3 (17p13.1), ...

Methods (2):

Molecular Genetics - Deletion/duplication analysis: Next-Generation (NGS)/Massively parallel sequencing (MPS); ...

Target population:

The target population for this test is patients suspected of …

Clinical validity:

Sung et al, 2003 identified a heterozygous missense mutation in …

Clinical utility:

Establish or confirm diagnosis

Ordering Information

Offered by:

Genetic Services Laboratory
View lab's website
View lab's test page

Specimen Source:

Buccal swab
Cell culture
Chorionic villi
Fetal blood
Fibroblasts
Peripheral (whole) blood
Saliva
View specimen requirements

Who can order:

Genetic Counselor
Health Care Provider
Licensed Physician
Nurse Practitioner
Physician Assistant
Registered Nurse

CPT codes:

81479

**AMA CPT codes notice

Contact Policy:

Laboratory can only accept contact from health care providers. Patients/families are encouraged to discuss genetic testing options with their health care provider.

How to Order:

All samples should be shipped via overnight delivery at room temperature.
No weekend or holiday deliveries.
Label each specimen with the patient’s name, date of birth and date sample collected.
Send specimens with complete requisition and consent form, otherwise, specimen processing may be delayed.
Order URL

Test service:

Clinical Testing/Confirmation of Mutations Identified Previously
Confirmation of research findings
Custom Deletion/Duplication Testing
Uniparental Disomy (UPD) Testing

Test additional service:

Custom Prenatal Testing
Custom mutation-specific/Carrier testing

Test development:

Test developed by laboratory (no manufacturer test name)

Informed consent required:

Pre-test genetic counseling required:

Decline to answer

Post-test genetic counseling required:

Decline to answer

Recommended fields not provided:

Test Order Code, Lab contact for this test, Test strategy

Conditions

Total conditions: 12

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 11

Gene	Associated Condition	Germline or Somatic	Allele (Lab-provided)	Variant in NCBI

Methodology

Total methods: 2

Method Category

Test method

Instrument *

Deletion/duplication analysis

Next-Generation (NGS)/Massively parallel sequencing (MPS)

Sequence analysis of the entire coding region

Next-Generation (NGS)/Massively parallel sequencing (MPS)

* Instrument: Not provided

Clinical Information

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; Pre-symptomatic; Risk Assessment; Screening

Clinical validity:

Sung et al, 2003 identified a heterozygous missense mutation in TPM2 in 1/14 probands with DA1A. Tajsharghi et al, 2007 identified a heterozygous missense mutations in TPM2 in a mother and daughter with DA2B. The TPM2 gene encodes betatropomyosin, an isoform of tropomyosin that is mainly expressed in slow, type … Sung et al, 2003 identified a heterozygous missense mutation in TPM2 in 1/14 probands with DA1A. Tajsharghi et al, 2007 identified a heterozygous missense mutations in TPM2 in a mother and daughter with DA2B. The TPM2 gene encodes betatropomyosin, an isoform of tropomyosin that is mainly expressed in slow, type 1 muscle fibers. Gurnett et al, 2010 identified two novel heterozygous missense mutations in MYBPC1 in two families with DA1B. MYBPC1 encodes for myosin binding protein and although the function of this protein has not been fully elucidated, it appears to be involved in the stabilization of sarcomere structures. Toydemir et al, 2006 identified mutations in MYH3 in 26/28 cases of patients with DA2A and 12/38 cases of patients with DA2B. Overall, mutations in MYH3 may account for approximately 90% of cases of DA2A and 40% of cases of DA2B. No mutations overlap between those that cause DA2A and DA2B. Sung et al, 2003 sequenced TNNT3 in 47 families with DA2B and identified a missense mutation in a woman with DA2B and her 2 affected daughters. TNNT3 is involved in the process of striated muscle contraction. Sung et al, 2003 identified two different missense mutations in 4/34 kindreds with DA2B. This protein is part of the multimeric troponin-tropomyosin-myosin complex of the sarcomere. McMillin et al, 2013, identified mutations in ECEL1 in five out of seven families with DA5D. Missense, frameshift, in-frame deletions and splicing mutations have all been reported. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Toydemir et al, 2006 identified a single missense mutation in MYH8 in four families with Trismus-pseudocamptodactyly syndrome (TPS). TPS is characterized by an inability to fully open the mouth and camptodactyly that is only apparent upon dorsiflexion of the wrists. Park et al, 1998 identified mutations in FBN2 in samples from 6/12 unrelated congenital contractural arachnodactyly (CCA) patients. CCA shares many phenotypic characteristics of neonatal Marfan syndrome including dolichostenomelia, arachnodactyly, scoliosis, pectus deformities and congenital contractures. In contract to Marfan syndrome, patients with CCA do not typically have ectopia lentis or aortic root dilatation. Sonoda et al, 2000 identified two brothers with multiple distal arthrogyposis, peculiar facial appearance, cleft palate, short stature, hydronephrosis, retention testis, and normal intelligence. Subsequent analysis of the CHST14 gene identified a homozygous missense mutation in these individuals. Mutations in CHST14 are implicated in Ehlers-Danlos syndrome, musculocontractural type, which is characterized by distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and scarring, wrinkled palms, joint hypermbolility and ocular involvement. McMillin et al, 2014 identified heterozygous mutations in PIEZO2 in 10 out of 12 patients (83%) with distal arthrogryposis type 3, a rare disorder characterized by cleft palate and multiple congenital contractures of the hands and feet (10). PIEZO2 mutations were also found in 24 out of 29 families (83%) with distal arthrogryposis type 5, which is associated with contractures, ocular abnormalities such as ophthalmoplegia, ptosis and/or strabismus, and pulmonary hypertension (10). View more

View citations (12)

Two brothers with distal arthrogryposis, peculiar facial appearance, cleft palate, short stature, hydronephrosis, retentio testis, and normal intelligence: a new type of distal arthrogryposis?. Sonoda T, et al. Am J Med Genet. 2000;91(4):280-5. PMID: 10766984.
Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Sung SS, et al. Am J Hum Genet. 2003;72(3):681-90. doi:10.1086/368294. PMID: 12592607.
Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Sung SS, et al. Am J Hum Genet. 2003;73(1):212-4. doi:10.1086/376418. PMID: 12865991.
Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006;38(5):561-5. doi:10.1038/ng1775. Epub 2006 Apr 16. PMID: 16642020.
Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8. Toydemir RM, et al. Am J Med Genet A. 2006;140(22):2387-93. doi:10.1002/ajmg.a.31495. PMID: 17041932.
Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation. Tajsharghi H, et al. Neurology. 2007;68(10):772-5. doi:10.1212/01.wnl.0000256339.40667.fb. PMID: 17339586.
Arthrogryposis: a review and update. Bamshad M, et al. J Bone Joint Surg Am. 2009;91 Suppl 4(Suppl 4):40-6. doi:10.2106/JBJS.I.00281. PMID: 19571066.
Gurnett CA, Desruisseau DM, McCall K, Choi R, Meyer ZI, Talerico M, Miller SE, Ju JS, Pestronk A, Connolly AM, Druley TE, Weihl CC, Dobbs MB. Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet. 2010;19(7):1165-73. doi:10.1093/hmg/ddp587. Epub 2010 Jan 02. PMID: 20045868.
Belaya K, Finlayson S, Slater CR, Cossins J, Liu WW, Maxwell S, McGowan SJ, Maslau S, Twigg SR, Walls TJ, Pascual Pascual SI, Palace J, Beeson D. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet. 2012;91(1):193-201. doi:10.1016/j.ajhg.2012.05.022. Epub 2012 Jun 27. PMID: 22742743.
McMillin MJ, Below JE, Shively KM, Beck AE, Gildersleeve HI, Pinner J, Gogola GR, Hecht JT, Grange DK, Harris DJ, Earl DL, Jagadeesh S, Mehta SG, Robertson SP, Swanson JM, Faustman EM, Mefford HC, Shendure J, Nickerson DA, Bamshad MJ, . Mutations in ECEL1 cause distal arthrogryposis type 5D. Am J Hum Genet. 2013;92(1):150-6. doi:10.1016/j.ajhg.2012.11.014. Epub 2012 Dec 20. PMID: 23261301.
McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA, , Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014;94(5):734-44. doi:10.1016/j.ajhg.2014.03.015. Epub 2014 Apr 10. PMID: 24726473.
Clustering of FBN2 mutations in patients with congenital contractural arachnodactyly indicates an important role of the domains encoded by exons 24 through 34 during human development. Park ES, et al. Am J Med Genet. 1998;78(4):350-5. PMID: 9714438.

Clinical utility:

Establish or confirm diagnosis

View citations (12)

Two brothers with distal arthrogryposis, peculiar facial appearance, cleft palate, short stature, hydronephrosis, retentio testis, and normal intelligence: a new type of distal arthrogryposis?. Sonoda T, et al. Am J Med Genet. 2000;91(4):280-5. PMID: 10766984.
Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Sung SS, et al. Am J Hum Genet. 2003;72(3):681-90. doi:10.1086/368294. PMID: 12592607.
Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Sung SS, et al. Am J Hum Genet. 2003;73(1):212-4. doi:10.1086/376418. PMID: 12865991.
Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006;38(5):561-5. doi:10.1038/ng1775. Epub 2006 Apr 16. PMID: 16642020.
Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8. Toydemir RM, et al. Am J Med Genet A. 2006;140(22):2387-93. doi:10.1002/ajmg.a.31495. PMID: 17041932.
Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation. Tajsharghi H, et al. Neurology. 2007;68(10):772-5. doi:10.1212/01.wnl.0000256339.40667.fb. PMID: 17339586.
Arthrogryposis: a review and update. Bamshad M, et al. J Bone Joint Surg Am. 2009;91 Suppl 4(Suppl 4):40-6. doi:10.2106/JBJS.I.00281. PMID: 19571066.
Gurnett CA, Desruisseau DM, McCall K, Choi R, Meyer ZI, Talerico M, Miller SE, Ju JS, Pestronk A, Connolly AM, Druley TE, Weihl CC, Dobbs MB. Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet. 2010;19(7):1165-73. doi:10.1093/hmg/ddp587. Epub 2010 Jan 02. PMID: 20045868.
Belaya K, Finlayson S, Slater CR, Cossins J, Liu WW, Maxwell S, McGowan SJ, Maslau S, Twigg SR, Walls TJ, Pascual Pascual SI, Palace J, Beeson D. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet. 2012;91(1):193-201. doi:10.1016/j.ajhg.2012.05.022. Epub 2012 Jun 27. PMID: 22742743.
McMillin MJ, Below JE, Shively KM, Beck AE, Gildersleeve HI, Pinner J, Gogola GR, Hecht JT, Grange DK, Harris DJ, Earl DL, Jagadeesh S, Mehta SG, Robertson SP, Swanson JM, Faustman EM, Mefford HC, Shendure J, Nickerson DA, Bamshad MJ, . Mutations in ECEL1 cause distal arthrogryposis type 5D. Am J Hum Genet. 2013;92(1):150-6. doi:10.1016/j.ajhg.2012.11.014. Epub 2012 Dec 20. PMID: 23261301.
McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA, , Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014;94(5):734-44. doi:10.1016/j.ajhg.2014.03.015. Epub 2014 Apr 10. PMID: 24726473.
Clustering of FBN2 mutations in patients with congenital contractural arachnodactyly indicates an important role of the domains encoded by exons 24 through 34 during human development. Park ES, et al. Am J Med Genet. 1998;78(4):350-5. PMID: 9714438.

Target population:

The target population for this test is patients suspected of having a diagnosis of Distal Arthrogryposis.

Variant Interpretation:

What is the protocol for interpreting a variation as a VUS?
Variants are identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors.

Will the lab re-contact the ordering physician if variant interpretation changes?
Yes.

Research:

Is research allowed on the sample after clinical testing is complete?
http://dnatesting.uchicago.edu/research-consent-form

Recommended fields not provided:

Are family members with defined clinical status recruited to assess significance of VUS without charge?, Sample negative report, Sample positive report

Technical Information

Availability:

Tests performed
Entire test performed in-house

Analytical Validity:

Analytical Sensitivity 99-100% Accuracy 100% Precision 100%

Assay limitations:

This assay covers the coding and immediate flanking regions of the included genes. Variants in the promoter region and in other non-coding regions will not be detected. Variants that occur within regions of high homology and/or repetitiveness may not be detected due to issues with alignment. The technical sensitivity of … View more

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Formal PT program

PT Provider:
American College of Medical Genetics / College of American Pathologists, ACMG/CAP

VUS:

Software used to interpret novel variations
A custom collection of bioinformatics tools

Laboratory's policy on reporting novel variations
The laboratory reports novel variations.

Recommended fields not provided:

Test Confirmation, Citations to support assay limitations, Description of internal test validation method, Citations for Analytical validity, Description of PT method, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Category: FDA exercises enforcement discretion

Additional Information

Reviews:

PubMed Clinical Queries

Clinical resources:

Molecular resources:

View TPM2 variations in ClinVar

RefSeqGene

Coriell Institute for Medical Research

Consumer resources:

Genetic Alliance

MalaCards

MedlinePlusGenetics (GHR)

MedlinePlus

IMPORTANT NOTE: NIH does not independently verify information submitted to GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in GTR. GTR is not a substitute for medical advice. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.