Facial Dysostosis Related Disorders Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10343 CREBBP 81407,81406 Order Options and Pricing
DHODH 81479,81479
EFTUD2 81479,81479
EP300 81479,81479
FGFR1 81405,81479
FGFR2 81479,81479
FGFR3 81479,81479
HDAC8 81479,81479
NIPBL 81479,81479
POLR1C 81479,81479
POLR1D 81479,81479
RAD21 81479,81479
SF3B4 81479,81479
SMC1A 81479,81479
SMC3 81479,81479
SRCAP 81479,81479
TCF12 81479,81479
TCOF1 81479,81479
TWIST1 81404,81403
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10343Genes x (19)81479 81403, 81404, 81405, 81406, 81407, 81479 $890 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 PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Facial dysostosis is a group of congenital craniofacial anomalies caused by abnormal development of the first and second pharyngeal arches during embryogenesis. This test combines four smaller panels which cover following disorders:

1: Craniosynostosis and Related Disorders: Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Crouzon syndrome, Apert syndrome, CATSHL syndrome, Muenke syndrome, Pfeiffer syndrome, Osteoglophonic dysplasia, Jackson-Weiss syndrome, Hartsfield syndrome, LADD syndrome, Saethre-Chotzen syndrome, and Bent bone dysplasia syndrome.

2: Treacher Collins syndrome, Mandibulofacial Dysostosis/, Miller syndrome and Acrofacial dysostosis, Nager type

3: Cornelia de Lange Syndrome

4: Rubinstein-Taybi syndrome and Floating-Harbor Syndrome

Genetics

This NextGen test analyzes multiple genes involved in Facial dysostosis related disorders as described in the clinical section.

Craniosynostosis and Related Disorders: FGFR1, FGFR2, FGFR3, TWIST1 and TCF12. These disorders are mainly inherited in an autosomal dominant manner, except for FGFR3-related CATSHL syndrome and FGFR1-relared Hartsfield syndrome, which can be inherited either in an autosomal dominant manner (mainly) or autosomal recessive manner. There is at least one reported autosomal recessive FGFR3-related CATSHL family and two reported FGFR1-related Hartsfield syndrome cases, respectively (Simonis et al. 2013; Makrythanasis et al. 2014).

Treacher Collins Syndrome: TCOF1, POLR1C, POLR1D. TCOF1-related Treacher Collins Syndrome is inherited in an autosomal dominant manner, while POLR1C-related Treacher Collins Syndrome is inherited in autosomal recessive manner. POLR1D related Treacher Collins Syndrome is mainly inherited in an autosomal dominant manner, except for two reported cases showed autosomal recessive inheritance.

Mandibulofacial Dysostosis: EFTUD2. Autosomal dominant.

Miller Syndrome: DHODH. Autosomal recessive.

Acrofacial dysostosis, Nager type: SF3B4. Autosomal dominant

Cornelia de Lange Syndrome (CdLS): NIPBL, SMC3, SMC1A, RAD21 and HDAC8. NIPBL, SMC3, and RAD21-related CdLS are inherited in autosomal dominant manner. SMC1A-related CdLSis inherited in an X-linked dominant manner (Deardorff et al. 2007). HDAC8-related CdLS is inherited in an X-linked manner, some HDAC8 heterozygous female carriers can be affected due to random X-inactivation (Deardorff et al. 2012).

Rubinstein-Taybi Syndrome: CREBBP and EP300. Autosomal dominant.

Floating-Harbor Syndrome: SRCAP. Autosomal dominant.

See individual gene test descriptions for information on clinical features of these disorders and molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

Craniosynostosis and Related Disorders:

~61% (111/182) of 182 Spanish craniosynostosis probands harbor a pathogenic variant in one of the FGFR2, FGFR3, TWIST1 and TCF12 genes. Pathogenic variants in FGFR2, FGFR3, TWIST and TCF12 account for 36%, 16%, 8% and 3% of pathogenic variants identified in this study, respectively (Paumard-Hernández et al. 2014).

TCF12 explains 32% and 10% of patients affected with bilateral and unilateral Craniosynostosis, respectively (Sharma et al. 2013).

One study reported that six unique FGFR1 pathogenic missense variants were found in seven unrelated patients affected with Hartsfield syndrome (Simonis et al. 2013). FGFR1 explains 5% of Pfeiffer syndrome type 1 cases (Robin et al. 2011).

Treacher Collins syndrome, Mandibulofacial Dysostosis/, Miller syndrome and Acrofacial dysostosis, Nager type:

TCOF1 pathogenic variants were found in ~70% of clinical diagnosed TCS cases, and large deletions are ~5% of reported TCOF1 pathogenic variants (Bowman et al. 2012; Katsanis and Jabs 2012).

POLR1D pathogenic variants were identified in 20 out of 242 (8%) unrelated TCS patients who were negative for TCOF1 variants. To date, only one large deletion has been reported (Dauwerse et al. 2010).

POLR1C pathogenic variants were identified in 3 out of 242 (~1%) unrelated patients with TCS or TCS phenotypic spectrum, who were negative for TCOF1 variants (Dauwerse et al. 2010).

Sequencing may detect up to 85% of disease causing mutations in clinically diagnosed Mandibulofacial Dysostosis, Guion-Almeida Type cases. Large deletion/insertions involving EFTUD2 cause ~15% of cases, which cannot be identified by sequencing (Lines 2012; Gordon et al. 2012; Need et al. 2012; Human Gene Mutation Database).

Rainger et al (2012) identified compound heterozygous pathogenic variants in DHODH in three out of eight unrelated families with Miller syndrome (Rainger et al. 2012).

Bernier et al. (2012) identified 18 different heterozygous SF3B4 pathogenic variants in 20 (57%) of 35 families affected by Acrofacial dysostosis, Nager type. Analytical sensitivity should be high because almost all of the documented SF3B4 pathogenic variants are point mutations, and small deletion/insertions which are expected to be detected by direct sequencing of genomic DNA.

Rubinstein-Taybi syndrome and Floating-Harbor Syndrome:

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).

Cornelia de Lange Syndrome:

Over 70% of all CdLS patients harbor a pathogenic variant in one of the five known CdLS genes (Boyle et al. 2014). This test does not detect large deletions or duplications spanning one or more exons.

Only five documented pathogenic variants in FGFR2 are large deletions/insertions (Human Gene Mutation Database; Bochukova et al. 2009). To date, no gross deletions or duplications have been reported in FGFR3 (Human Gene Mutation Database). Intragenic NIPBL deletions and a duplication were identified in 13 (2.5%) out of 510 CdLS cases (12 deletions and 1 duplication) (Cheng et al. 2014). Large deletions and duplications account for 11% of reported SMC1A pathogenic variants (Gilissen et al. 2014; Baquero-Montoya et al. 2014). There are no reported large deletions or duplications in SMC3 (Human Gene Mutation Database).

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this test are patients with clinical and radiologic features consistent with Facial dysostosis related disorders.

Genes

Official Gene Symbol OMIM ID
CREBBP 600140
DHODH 126064
EFTUD2 603892
EP300 602700
FGFR1 136350
FGFR2 176943
FGFR3 134934
HDAC8 300269
NIPBL 608667
POLR1C 610060
POLR1D 613715
RAD21 606462
SF3B4 605593
SMC1A 300040
SMC3 606062
SRCAP 611421
TCF12 600480
TCOF1 606847
TWIST1 601622
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Baquero-Montoya C, Gil-Rodríguez M c., Teresa-Rodrigo M e., Hernández-Marcos M, Bueno-Lozano G, Bueno-Martínez I, Remeseiro S, Fernández-Hernández R, Bassecourt-Serra M, Rodríguez de Alba M, Queralt E, Losada A, et al. 2014. Could a patient with SMC1A duplication be classified as a human cohesinopathy? Clin Genet 85: 446–451. PubMed ID: 23683030
  • Bernier et al. 2012. PubMed ID: 22541558
  • Bochukova EG, Roscioli T, Hedges DJ, Taylor IB, Johnson D, David DJ, Deininger PL, Wilkie AOM. 2009. Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. Hum. Mutat. 30: 204–211. PubMed ID: 18726952
  • Bowman et al. 2012. PubMed ID: 22317976
  • Boyle M i., Jespersgaard C, Brøndum-Nielsen K, Bisgaard A-M, Tümer Z. 2014. Cornelia de Lange syndrome. Clin Genet n/a-n/a. PubMed ID: 25209348
  • Cheng Y-W, Tan CA, Minor A, Arndt K, Wysinger L, Grange DK, Kozel BA, Robin NH, Waggoner D, Fitzpatrick C, Das S, Gaudio D del. 2014. Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion. Mol Genet Genomic Med 2: 115-123. PubMed ID: 24689074
  • Dauwerse et al. 2011. PubMed ID: 21131976
  • Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, Baere E De, et al. 2012. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489: 313–317. PubMed ID: 22885700
  • Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Rodríguez C, Arnedo M, Loeys B, Kline AD, Wilson M, Lillquist K, Siu V, Ramos FJ, Musio A, Jackson LS, Dorsett D, Krantz ID. 2007. Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia de Lange Syndrome with Predominant Mental Retardation. The American Journal of Human Genetics 80: 485–494. PubMed ID: 17273969
  • Gilissen C, Hehir-Kwa JY, Thung DT, Vorst M van de, Bon BWM van, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. 2014. Genome sequencing identifies major causes of severe intellectual disability. Nature 511: 344-347. PubMed ID: 24896178
  • Gordon et al. 2012. PubMed ID: 23188108
  • Human Gene Mutation Database (Bio-base).
  • Katsanis and Jabs. 2018. PubMed ID: 20301704
  • 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
  • Lines, M. A. et al., (2012). PubMed ID: 22305528
  • Makrythanasis P, Temtamy S, Aglan MS, Otaify GA, Hamamy H, Antonarakis SE. 2014. A Novel Homozygous Mutation in FGFR3 Causes Tall Stature, Severe Lateral Tibial Deviation, Scoliosis, Hearing Impairment, Camptodactyly, and Arachnodactyly. Human Mutation 35: 959-963. PubMed ID: 24864036
  • Need, A. C. et al., (2012). PubMed ID: 22581936.
  • Paumard-Hernández B, Berges-Soria J, Barroso E, Rivera-Pedroza CI, Pérez-Carrizosa V, Benito-Sanz S, López-Messa E, Santos F, García-Recuero II, Romance A, Ballesta-Martínez JM, López-González V, Campos-Barros A, Cruz J5, Guillén-Navarro E, Sánchez Del Pozo J, Lapunzina P, García-Miñaur S, Heath KE. 2014. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants. European Journal of Human Genetics. PubMed ID: 25271085
  • Rainger et al. 2012. PubMed ID: 22692683
  • Robin NH, Falk MJ, Haldeman-Englert CR. 2011. FGFR-Related Craniosynostosis Syndromes. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301628
  • Sharma VP, Fenwick AL, Brockop MS, McGowan SJ, Goos JAC, Hoogeboom AJM, Brady AF, Jeelani NO, Lynch SA, Mulliken JB, Murray DJ, Phipps JM, Sweeney E, Tomkins SE, Wilson LC, Bennett S, Cornall RJ, Broxholme J, Kanapin A; 500 Whole-Genome Sequences (WGS500) Consortium, Johnson D, Wall SA, van der Spek PJ, Mathijssen IM, Maxson RE, Twigg SR, Wilkie AO. 2013. Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nat Genet 45: 304-307. PubMed ID: 23354436
  • Simonis N, Migeotte I, Lambert N, Perazzolo C, Silva DC de, Dimitrov B, Heinrichs C, Janssens S, Kerr B, Mortier G, Vliet G Van, Lepage P, Casimir G, Abramowicz M, Smits G, Vilain C. 2013. FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. Journal of Medical Genetics 50: 585–592. PubMed ID: 23812909
  • 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

Ordering/Specimens

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For Requisition Forms, visit our Forms page


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