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Coffin-Siris Syndrome Sequencing Panel

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

NextGen Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
2633 ARID1A 81479 Add to Order
ARID1B 81479
SMARCA4 81479
SMARCB1 81479
SMARCE1 81479
SOX11 81479
Full Panel Price* $640.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
2633 Genes x (6) $640.00 81479(x6) 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

This test is expected to detect causative variants in about 60% of patients with Coffin-Siris Syndrome (Vergano et al. 2013).

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Del/Dup via aCGH

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
600 ARID1A$990.00 81479 Add to Order
ARID1B$990.00 81479
SMARCA4$990.00 81479
SMARCB1$990.00 81479
SMARCE1$990.00 81479
Full Panel Price* $1190.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (5) $1190.00 81479(x5) Add to Order
Pricing Comments

# of Genes Ordered

Total Price

1

$990

2-5

$1190

6-10

$1290

11-100

$1490

Over 100

Call for quote
Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

It is difficult to estimate the clinical senitivity of this test due to the lack of large cohort studies. Gross deletions have been found in the ARID1A, ARID1B, SMARCA4 and SOX11 genes that cause Coffin-Siris Syndrome.

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Clinical Features

Coffin-Siris syndrome (CSS) is a multi-systemic genetic disease characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, mild to severe developmental delay, intellectual disability, distinctive facial features, and sparse scalp hair. Other variable findings include short stature, feeding difficulties, ophthalmologic abnormalities, cardiac anomalies and hearing loss (Vergano et al. 2013; Vergano and Deardorff 2014).

To date, fewer than 200 cases of confirmed CSS have been clinically reported. The exact prevalence and incidence is not clear, but this disorder is probably underestimated. The diagnosis is generally based on the presence of major and minor clinical signs. Due to clinically heterogeneous features, CSS is sometimes misdiagnosed. Molecular genetic testing is particularly useful to reach an accurate diagnosis (Vergano et al. 2013).

Genetics

CSS is inherited in an autosomal dominant (AD) manner with high penetrance. Most patients reported to date had a de novo pathogenic variant. Pathogenic variants or genomic rearrangements in the following genes have been reported to be causative for CSS: ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11 (Kosho et al. 2014a; Hempel et al 2016). These genes encode human homologs of proteins in the BRG1- and BRM-associated factor (BAF) complex, which is also known as the mammalian switch/sucrose non-fermentable (mSWI/SNF)-like nucleosome remodeling complex. This complex is involved in the destabilization of histone-DNA interactions in an ATP-dependent manner, which is important for the expression of genes normally suppressed by chromatin (Ronan et al. 2013; Kosho et al. 2014b).

Pathogenic variants in the ARID1B gene are the most common cause of CSS (Wieczorek et al. 2013). ARID1A and ARID1B encode AT-rich interactive domain-containing proteins. These proteins function as alternative, mutually exclusive subunits of the SWI/SNF complex (Watanabe et al. 2014). Previous studies suggest that pathogenic variants in ARID1A and ARID1B may cause aberrant chromatin remodeling with a loss-of-function mechanism. SMARCA4, SMARCB1 and SMARCE1 belong to the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin family. The exact mechanisms of these genes in the pathology of CSS are currently not clear, but pathogenic variants in these genes may have a gain-of function or dominant-negative effect (Kosho et al. 2014b). Pathogenic variants in another gene, SOX11, have also been reported to cause CSS. SOX11 is a transcription factor downstream of the BAF complex and plays an important role in neurogenesis during brain development (Tsurusaki et al. 2014; Hempel et al. 2016).

Heterozygous pathogenic variants in SMARCA4 and SMARCB1 genes have also been reported to cause the rhabdoid tumor predisposition syndrome (Roberts and Biegel 2009; Hasselblatt et al. 2011; Biegel et al. 2014).

Testing Strategy

For this NGS test, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for each of the genes listed. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization method, 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. All pathogenic, undocumented and questionable variant calls are confirmed by Sanger sequencing.

This panel provides 100% coverage of the aforementioned regions of the indicated genes. We define 100% coverage as > 20X NGS reads for exons and 0-10 bases of flanking DNA, > 10X NGS reads for 11-20 bases of flanking DNA, or Sanger sequencing.

Indications for Test

Individuals with symptoms consistent with Coffin-Siris Syndrome are candidates for this test.

Genes

Official Gene Symbol OMIM ID
ARID1A 603024
ARID1B 614556
SMARCA4 603254
SMARCB1 601607
SMARCE1 603111
SOX11 600898
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Familial Meningioma via SMARCE1 Gene Sequencing with CNV Detection
Ovarian Cancer and Rhabdoid Tumor Predisposition Syndrome via SMARCA4 Gene Sequencing with CNV Detection
Rhabdoid Tumor Predisposition Syndrome via SMARCB1 Gene Sequencing with CNV Detection

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Biegel J.A. et al. 2014. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 166C: 350-66. PubMed ID: 25169151
  • Hasselblatt M. et al. 2011. The American Journal of Surgical Pathology. 35: 933-5. PubMed ID: 21566516
  • Hempel A. et al. 2016. Journal of Medical Genetics. 53: 152-62. PubMed ID: 26543203
  • Kosho T. et al. 2014a. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 166C: 241-51. PubMed ID: 25169878
  • Kosho T. et al. 2014b. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 166C: 262-75. PubMed ID: 25168959
  • Roberts C.W., Biegel J.A. 2009. Cancer Biology & Therapy. 8: 412-6. PubMed ID: 19305156
  • Ronan J.L. et al. 2013. Nature Reviews. Genetics. 14: 347-59. PubMed ID: 23568486
  • Tsurusaki Y. et al. 2014. Nature Communications. 5: 4011. PubMed ID: 24886874
  • Vergano S. et al. 2013. Coffin-Siris Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 23556151
  • Vergano S.S., Deardorff M.A. 2014. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 166C: 252-6. PubMed ID: 25169447
  • Watanabe R. et al. 2014. Cancer Research. 74: 2465-75. PubMed ID: 24788099
  • Wieczorek D. et al. 2013. Human Molecular Genetics. 22: 5121-5135. PubMed ID: 23906836
Order Kits
TEST METHODS

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 (http://www.hgvs.org).  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 extracted and 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. PreventionGenetics has established and verified this test's accuracy and precision.

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.

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

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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.
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.
SPECIMEN TYPES
WHOLE BLOOD

(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.
DNA

(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.
CELL CULTURE

(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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