Distal Arthrogryposis Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits


Test Code Test Copy GenesCPT Code Copy CPT Codes
1999 CHST14 81479 Add to Order
ECEL1 81479
FBN2 81479
MYBPC1 81479
MYH3 81479
MYH8 81479
NALCN 81479
PIEZO2 81479
TNNI2 81479
TNNT3 81479
TPM2 81479
Full Panel Price* $710
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1999 Genes x (11) $710 81479(x11) Add to Order
Pricing Comments

We are happy to accommodate requests for single genes or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered on our PGxome Custom Panel.

Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

MYH3 pathogenic variants appear to be a common cause of FSS and SHS. Pathogenic variants in MYH3 contribute approximately 90% of the cases of FSS and 40% of SHS cases (Bamshad et al. 2009). Pathogenic MYH3 variants were found in 26 of 28 cases (FSS or SHS), 75% of which were sporadic (Toydemir et al. 2006). TNNI2 appears to be a less common cause of SHS than MYH3 (Toydemir et al. 2006). Among 47 Distal Arthrogryposis families, one was found to have a TNNT3 pathogenic variant (Sung et al. 2003). Variants in CHST14, ECEL1, FBN2, MYBPC1, MYH8, NALCN, PIEZO2 and TPM2 have been reported in individual cases associated with Distal Arthrogryposis, and appear to be infrequent causes of disease.

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CNV via aCGH

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
600 ECEL1$990 81479 Add to Order
FBN2$990 81479
MYH3$990 81479
NALCN$990 81479
TNNI2$990 81479
TNNT3$990 81479
TPM2$990 81479
Full Panel Price* $1290
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (7) $1290 81479(x7) Add to Order
Pricing Comments

# of Genes Ordered

Total Price









Over 100

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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

Among the 11 genes in Distal Arthrogryposis NGS panel, gross deletions or duplications not detectable by Sanger sequencing were only reported in FBN2 and NALCN as individual cases, and no statistical data is yet available (Human Gene Mutation Database).

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Clinical Features

Distal arthrogryposis (DA) syndromes are a group of multiple congenital contracture disorders with distal joint involvement, variable clinical expression, and most often autosomal dominant inheritance (Bamshad et al. 1996). Distal arthrogryposis 2A (DA2A), also called Freeman-Sheldon syndrome (FSS), is the most severe DA syndrome. Patients with FSS have, in addition to distal joint contractures, facial findings secondary to contractures of facial muscles. A small mouth with a whistling-like appearance is a universal finding. The eyes are often deep-set and the nasal bridge wide. Other findings include epicanthal folds, strabismus, bilateral ptosis and reduced eyelid size. FSS patients also often have H-shaped dimpling of the chin, small nose, long philtrum, high palate, small tongue, and nasal speech. Skeletal findings include ulnar deviation of the hands, camptodactyly, kyphoscoliosis, clubfoot, and contractures of the knees or hips. Distal arthrogryposis 2B (DA2B), or Sheldon-Hall syndrome (SHS) is the most common DA syndrome. Clinically, SHS is less severe than FSS, but more severe than TPM2-related DA (DA1). Facial features reminiscent of FSS are present, but are less pronounced. Distal arthrogryposis 1A (DA1A) is characterized clinically by clubfoot, camptodactyly, and hypoplasia or absence of interphalangeal creases. Although the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable (Bamshad et al. 2009). As a result of phenotypic and genotypic overlap, it has been proposed that DA1A and DA2B represent extremes of a single clinical entity (Beck at al. 2013). Distal arthrogryposis type 5D (DA5D) is an autosomal recessive DA syndrome with unique facial features (McMillin et al. 2013). Arthrogryposis DA5D affects the distal joints as well as extension contractures of the knee. Camptodacytly is more severe in the fingers than the toes with the wrist and thumbs being adducted. The feet are affected by talipes equinovarus and/or calcaneovalgus deformity. Facial findings include ptosis, which can be unilateral or more severe on one side, micrognathia, arched eye-brows, a bulbous nose that is upturned, and an over-all rounded face. Unlike other DA5 phenotypes, ophthalmoplegia is not a finding of DA5D (McMillin et al. 2013).


Distal Arthrogryposes (DA) is a major subgroup of heterogeneous disorders of Arthrogryposis multiplex congenital (AMC). At least ten different forms of DA (DA1-10) have been reported, and DA1, DA2B (Sheldon-Hall syndrome) and DA2A (Freeman-Sheldon syndrome) are the most common DAs (Bamshad et al. 2009). Genes associated with DA encode components of the contractile apparatus of skeletal muscle. Variants in MYH3 are the most common known cause of DA (Toydemir et al. 2006). This panel includes 11 genes associated with DA: CHST14, ECEL1, FBN2, MYBPC1, MYH3, MYH8, NALCN, PIEZO2, TNNI2, TNNT3 and TPM2. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, except that ECEL and CHST14 pathogenic variants are inherited in an autosome recessive manner (McMillin et al. 2013; Sonoda et al. 2000). A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Large deletions/duplications and complex genomic rearrangements have also been reported in two genes (FBN2 and NALCN) (Human Gene Mutation Database). See individual gene test descriptions for more information on molecular biology of gene products, and spectra of pathogenic variants.

Testing Strategy

For this Next Generation (NextGen) panel, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for each of the genes listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads.

Indications for Test

Individuals with clinical symptoms consistent with distal arthrogryposis syndromes.


Official Gene Symbol OMIM ID
CHST14 608429
ECEL1 605896
FBN2 612570
MYBPC1 160794
MYH3 160720
MYH8 160741
NALCN 611549
PIEZO2 613629
TNNI2 191043
TNNT3 600692
TPM2 190990
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

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Genetic Counselors
  • Bamshad M. et al. 1996. American Journal of Medical Genetics. 65: 277-81. PubMed ID: 8923935
  • Bamshad M. et al. 2009. The Journal of Bone and Joint Surgery. American Volume. 91 Suppl 4: 40-6. PubMed ID: 19571066
  • Beck A.E. et al. 2013. American Journal of Medical Genetics. Part A. 161A: 550-5. PubMed ID: 23401156
  • Human Gene Mutation Database (Bio-base).
  • McMillin MJ. et al. 2013. American Journal of Human Genetics. 92: 150-6. PubMed ID: 23261301
  • Sonoda T., Kouno K. American Journal of Medical Genetics. 91:280-5. PubMed ID: 10766984
  • Sung S.S. et al. 2003. American Journal of Human Genetics. 72: 681-90. PubMed ID: 12592607
  • Toydemir R.M. et al. 2006. Nature Genetics. 38: 561-5. PubMed ID: 16642020
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NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~10 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are often covered by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~10 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

In the case of duplications, aCGH will not determine the chromosomal location of the duplicated DNA. Most duplications will be tandem, but in some cases the duplicated DNA will be inserted at a different locus. This method will also not determine the orientation of the duplicated segment (direct or inverted).

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay is dependent upon the quality of the input DNA. In particular, highly degraded DNA will yield poor results.

Order Kits

Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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