Rubinstein-Taybi Syndrome and Floating-Harbor Syndrome Panel
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Panel CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 10141 | Genes x (3) | 81479 | 81406(x1), 81407(x1), 81479(x4) | $990 | Order Options and Pricing |
Pricing Comments
We are happy to accommodate requests for testing single genes in this panel 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 via our Custom Panel tool.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Rubinstein-Taybi syndrome (also called broad Thumbs-Hallux Syndrome) is characterized by short stature, distinctive facial features, broad thumbs and big toes, moderate to severe intellectual disability and postnatal growth retardation. Other features include cryptorchidism, microcephaly, speech delay, delayed bone age, gastroesophageal reflux, coloboma, renal abnormalities and congenital heart defects. The prevalence is ~ 1/125,000 live births (Stevens 2014; Milani et al. 2015).
Floating-Harbor syndrome is a rare short stature syndrome with delayed osseous maturation, expressive language impairments, typical facial dysmorphism, and intellectual disability (Nikkel et al. 2013). Floating-Harbor syndrome shares some features with Rubinstein-Taybi syndrome, such as short stature, a long nose with low-hanging columella, a thin vermilion border of the upper lip, and anomalous thumbs.
Genetics
Rubinstein-Taybi syndrome is inherited in an autosomal dominant manner and is caused by pathogenic variants in the CREBBP and EP300 genes.
Floating-Harbor syndrome is inherited in an autosomal dominant manner and is caused by pathogenic variants in the SRCAP gene.
~250 unique CREBBP pathogenic variants have been reported. They include: missense (16%), nonsense (16%), splicing (8%), small deletion/insertion (29%), gross deletion (19%), gross duplication (10%) and 3 unique translocations involving CREBBP (Petrij et al. 2000; Thienpont et al. 2007; Tsai et al. 2011; Demeer et al. 2013). CREBBP intragenic deletions were identified in 7 out of 75 patients with Rubinstein–Taybi syndrome by MLPA analysis (Aradhya et al. 2012). Interstitial 16p13.3 duplications of the critical Rubinstein region were found in patients with intellectual disability & multiple congenital anomalies, and 8 out 9 these duplications arose de novo (Thienpont et al. 2010; Demeer et al. 2013).
Less than 20 unique EP300 pathogenic variants for Rubinstein-Taybi syndrome have been reported. They include: nonsense (2), splicing (1), small deletion and duplication (8), and large deletion involving single or multiple exons (5) (Tsai et al. 2011; Roelfsema et al. 2005; Solomon et al. 2015 and Negri et al. 2015). Most pathogenic variants in the EP300 gene occur de novo (Woods et al. 2014).
CREBBP and EP300 proteins, coded by CREBBP and EP300, respectively, are transcriptional adaptors and histone acetyltransferases that acetylate nucleosomes (Ogryzko et al. 1996).
SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREBBP, the major gene for Rubinstein-Taybi syndrome. All the reported pathogenic variants are located in exon 34 resulting in truncation of SRCAP protein (nonsense: 32%, small deletion/insertion: 68%) except one in exon 33. The c.7330C>T, p.Arg2444* and c.7303C>T, p.Arg2435* are recurrent variants which were found in about 46% and 25% of the studied patients, respectively (Nikkel et al. 2013). At least 5 out of 13 patients had a de novo pathogenic variant (Hood et al. 2012). No large deletions and insertions have been identified.
Clinical Sensitivity - Sequencing with CNV PGxome
Sequence analysis can detect CREBBP pathogenic variants in 40%-50% of Rubinstein-Taybi syndrome cases. Pathogenic variants in EP300 are identified in ~3%-8% of patients with Rubinstein–Taybi syndrome (Stevens 2014). 16p13.3 microdeletions (size ranging from 3.3kb to 3900kb) involving CREBBP were found 17 out of 83 patients with typical features of Rubinstein–Taybi syndrome using array CGH and quantitative multiplex fluorescent-PCR (Stef et al. 2007). In one study, SRCAP pathogenic variants were found in 6 out of 9 patients with Floating-Harbor syndrome (Le Goff et al. 2013).
Testing Strategy
This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.
This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).
Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).
Indications for Test
Candidates for this test are patients with symptoms consistent with Rubinstein-Taybi syndrome, Floating-Harbor syndrome and family members of patients who have known CREBBP, EP300 and SRCAP pathogenic variants (Stevens 2014; Hood et al. 2012).
Candidates for this test are patients with symptoms consistent with Rubinstein-Taybi syndrome, Floating-Harbor syndrome and family members of patients who have known CREBBP, EP300 and SRCAP pathogenic variants (Stevens 2014; Hood et al. 2012).
Genes
| Official Gene Symbol | OMIM ID |
|---|---|
| CREBBP | 600140 |
| EP300 | 602700 |
| SRCAP | 611421 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Floating-Harbor Syndrome | AD | 136140 |
| Rubinstein-Taybi Syndrome | AD | 180849 |
| Rubinstein-Taybi Syndrome 2 | AD | 613684 |
Related Test
| Name |
|---|
| PGxome® |
Citations
- Aradhya S, Lewis R, Bonaga T, Nwokekeh N, Stafford A, Boggs B, Hruska K, Smaoui N, Compton JG, Richard G, Suchy S. 2012. Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders. Genetics in Medicine 14: 594-603. PubMed ID: 22382802
- Demeer B, Andrieux J, Receveur A, Morin G, Petit F, Julia S, Plessis G, Martin-Coignard D, Delobel B, Firth HV, Thuresson AC, Lanco dosen S, Sjörs K, Le Caignec C, Devriendt K, Mathieu-Dramard M. 2013. Duplication 16p13.3 and the CREBBP gene: Confirmation of the phenotype. European Journal of Medical Genetics 56: 26-31. PubMed ID: 23063576
- Hood RL, Lines MA, Nikkel SM, Schwartzentruber J, Beaulieu C, Nowaczyk MJM, Allanson J, Kim CA, Wieczorek D, Moilanen JS, Lacombe D, Gillessen-Kaesbach G, Whiteford ML, Quaio CR, Gomy I, Bertola DR, Albrecht B, Platzer K, McGillivray G, Zou R, McLeod DR, Chudley AE, Chodirker BN, Marcadier J; FORGE Canada Consortium, Majewski J, Bulman DE, White SM, Boycott KM. 2012. Mutations in SRCAP, Encoding SNF2-Related CREBBP Activator Protein, Cause Floating-Harbor Syndrome. Am J Hum Genet 90: 308-313. PubMed ID: 22265015
- Le Goff C, Mahaut C, Bottani A, Doray B, Goldenberg A, Moncla A, Odent S, Nitschke P, Munnich A, Faivre L, Cormier-Daire V. 2013. Not All Floating-Harbor Syndrome Cases are Due to Mutations in Exon 34 of SRCAP. Human Mutation 34: 88–92. PubMed ID: 22965468
- Milani D, Manzoni FMP, Pezzani L, Ajmone P, Gervasini C, Menni F, Esposito S. 2015. Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management. Ital J Pediatr 41: PubMed ID: 4308897
- Negri G, Milani D, Colapietro P, Forzano F, Della Monica M, Rusconi D, Consonni L, Caffi LG, Finelli P, Scarano G, Magnani C, Selicorni A, Spena S, Larizza L, Gervasini C. 2015. Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene. Clin Genet 87: 148-154. PubMed ID: 24476420
- Nikkel SM, Dauber A, Munnik S de, Connolly M, Hood RL, Caluseriu O, Hurst J, Kini U, Nowaczyk MJM, Afenjar A, Albrecht B, Allanson JE, Balestri P, Ben-Omran T, Brancati F, Cordeiro I, da Cunha BS, Delaney LA, Destrée A, Fitzpatrick D, Forzano F, Ghali N, Gillies G, Harwood K, Hendriks YM, Héron D, Hoischen A, Honey EM, Hoefsloot LH, Ibrahim J, Jacob CM, Kant SG, Kim CA, Kirk EP, Knoers NV, Lacombe D, Lee C, Lo IF, Lucas LS, Mari F, Mericq V, Moilanen JS, Mřller ST, Moortgat S, Pilz DT, Pope K, Price S, Renieri A, Sá J, Schoots J, Silveira EL, Simon ME, Slavotinek A, Temple IK, van der Burgt I, de Vries BB, Weisfeld-Adams JD, Whiteford ML, Wierczorek D, Wit JM, Yee CF, Beaulieu CL; FORGE Canada Consortium, White SM, Bulman DE, Bongers E, Brunner H, Feingold M, Boycott KM. 2013. The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP. Orphanet J Rare Dis 8: 63. PubMed ID: 23621943
- Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. 1996. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87: 953-959. PubMed ID: 8945521
- Petrij F, Dorsman JC, Dauwerse HG, Giles RH, Peeters T, Hennekam RCM, Breuning MH, Peters DJM. 2000. Rubinstein-Taybi syndrome caused by a de novo reciprocal translocation t(2;16)(q36.3;p13.3). Am. J. Med. Genet. 92: 47-52. PubMed ID: 10797422
- Roelfsema JH, White SJ, Ariyürek Y, Bartholdi D, Niedrist D, Papadia F, Bacino CA, Dunnen JT den, Ommen G-JB van, Breuning MH, Hennekam RC, Peters DJM. 2005. Genetic Heterogeneity in Rubinstein-Taybi Syndrome: Mutations in Both the CBP and EP300 Genes Cause Disease. Am J Hum Genet 76: 572-580. PubMed ID: 15706485
- Solomon BD, Bodian DL, Khromykh A, Mora GG, Lanpher BC, Iyer RK, Baveja R, Vockley JG, Niederhuber JE. 2015. Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome. Am. J. Med. Genet. 167: 1111-1116. PubMed ID: 25712426
- Stef M, Simon D, Mardirossian B, Delrue M-A, Burgelin I, Hubert C, Marche M, Bonnet F, Gorry P, Longy M, Lacombe D, Coupry I, Arveiler B. 2007. Spectrum of CREBBP gene dosage anomalies in Rubinstein–Taybi Syndrome patients. Eur J Hum Genet 15: 843–847. PubMed ID: 17473832
- Stevens CA. 2014. Rubinstein-Taybi Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301699
- Thienpont B, Béna F, Breckpot J, Philip N, Menten B, Esch HV, Scalais E, Salamone JM, Fong C-T, Kussmann JL, Grange DK, Gorski JL, Zahir F, Yong SL, Morris MM, Gimelli S, Fryns JP, Mortier G, Friedman JM, Villard L, Bottani A, Vermeesch JR, Cheung SW, Devriendt K. 2010. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet 47: 155-161. PubMed ID: 19833603
- Thienpont B, Breckpot J, Holvoet M, Vermeesch JR, Devriendt K. 2007. A microduplication of CBP in a patient with mental retardation and a congenital heart defect. Am. J. Med. Genet. 143A: 2160-2164. PubMed ID: 17702016
- Tsai AC-H, Dossett CJ, Walton CS, Cramer AE, Eng PA, Nowakowska BA, Pursley AN, Stankiewicz P, Wiszniewska J, Cheung SW. 2011. Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein-Taybi syndrome detected by aCGH. Eur. J. Hum. Genet. 19: 43-49. PubMed ID: 20717166
- Woods S.A. et al. 2014. American Journal of Medical Genetics. Part A. 164A: 251-8. PubMed ID: 24352918
Ordering/Specimens
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myPrevent - Online Ordering
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Requisition Form
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For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
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