Treacher Collins Syndrome/Mandibulofacial Dysostosis/Miller Syndrome/Acrofacial Dysostosis, Nagar Type Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10235 DHODH 81479,81479 Order Options and Pricing
EFTUD2 81479,81479
POLR1B 81479,81479
POLR1C 81479,81479
POLR1D 81479,81479
SF3B4 81479,81479
TCOF1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10235Genes x (7)81479 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

Treacher Collins syndrome (TCS, also called mandibulofacial dysostosis or Franceschetti-Kelin syndrome) is a birth defect of craniofacial morphogenesis with an estimated prevalence of 1:50,000 live births (Trainor et al. 2009. PubMed ID: 19107148). TCS is characterized by downward slanting palpebral fissures, lower eyelid colobomas, microtia, and malar and mandibular hypoplasia. Other features include cleft palate, malformation of external ear canals, and bilateral conductive hearing loss (Dixon. 1996. PubMed ID: 8875242; Chang and Steinbacher. 2012. PubMed ID: 23633935). Clinical presentations of TCS are highly variable. TCS shares some facial dysmorphic features with other syndromes such as Pierre-Robin, Miller, Nager, and Goldenhar syndromes. It can be further divided into four subtypes: TCS type 1 is inherited in an autosomal dominant manner and is caused by pathogenic variants in TCOF1. TCS type 2 is inherited in both autosomal dominant and autosomal recessive manners and is caused by pathogenic variants in POLR1D. TCS type 3 is inherited in an autosomal recessive form and is caused by pathogenic variants in POLR1C (Dixon. 1996. PubMed ID: 8875242; Dauwerse et al. 2011. PubMed ID: 21131976; Katsanis and Jabs. 2018. PubMed ID: 20301704; Schaefer et al. 2014. PubMed ID: 24603435). TCS type 4 is inherited in autosomal dominant manner and is caused by missense variants in the POLR1B gene (Sanchez et al. 2020. PubMed ID: 31649276).

Mandibulofacial Dysostosis, Guion-Almeida Type (MFDGA, also called mandibulofacial dysostosis with microcephaly) is a multiple malformation syndrome characterized by progressive microcephaly, choanal atresia, cleft palate, mandibular hypoplasia, microtia, preauricular tags, conductive deafness, congenital heart and/ or thumb anomalies and developmental delay (Wieczorek et al. 2009. PubMed ID: 19334086; Lines et al. 2012). Phenotypes of mandibulofacial dysostosis overlap with other syndromes such as Pierre-Robin, Miller, Treacher Collins, and Nager syndromes, as well as oculoauriculovertebral (OAVS) spectrum disorders such as VATER association, CHARGE, Goldenhar and Feingold syndromes (Lines et al. 2012. PubMed ID: 22305528; Gordon et al. 2012. PubMed ID: 23188108; Need et al. 2012. PubMed ID: 22581936).

Miller syndrome (also called postaxial acrofacial dystosis, Genee-Wiedemann syndrome, and Wildervanck-Smith syndrome) is characterized by dysmorphic craniofacial features with postaxial limb deformities (Donnai et al. 1987. PubMed ID: 3612717). The most common features include severe micrognathia, cleft lip and/or palate, absence of fifth fingers and toes, syndactyly, abnormal bones in the forearms and lower legs, coloboma of the eyelids, and supernumerary nipples. Other dysmorphic features include downward slanting palpebral fissures, malar hypoplasia, malformed ears and a broad nasal ridge. The less common features include abnormalities of the heart, kidneys, genitalia, or gastrointestinal tract. Patients may show delayed speech development due to hearing impairment, but usually their intelligence is normal. Other syndromes such as Pierre-Robin, Treacher-Collins, and Franschetti-Klein share facial features with Miller syndrome.

Acrofacial dysostosis, Nager type is characterized by malformation of the craniofacial area and the limbs. The major craniofacial features are: downslanted palpebral fissures, midface retrusion, and micrognathia. The upper limb defects consist of small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Some other features include, but are not limited to, cleft palate, tracheotomy and hearing loss. Acrofacial dysostosis, Nager type shares some features with Miller syndrome (Bernier et al. 2012. PubMed ID: 22541558).

Molecular genetic testing is advantageous to establish an accurate diagnosis for individuals with TCS or related conditions.

Genetics

TCS Type 1 is inherited in an autosomal dominant manner and is caused by pathogenic variants in the TCOF1 gene. To date, more than 200 unique causative variants have been identified in TCS patients. These variants are: missense (4%), nonsense (23%), splicing (16%), small deletion/insertions (57%) and large deletion (5%). ~60% of affected individuals have a de novo TCOF1 variant (Beygo et al. 2012. PubMed ID: 22712005; Bowman et al. 2012. PubMed ID: 22317976; Human Gene Mutation Database; Katsanis and Jabs. 2018. PubMed ID: 20301704; Vincent et al. 2014. PubMed ID: 23695276).

TCS Type 2 (POLR1D-related TCS) is mainly inherited in an autosomal dominant manner; only two reported cases were inherited in an autosomal recessive manner (Schaefer et al. 2014. PubMed ID: 24603435).To date, ~20 unique causative variants have been identified in 20 unrelated index TCS patients. These variants are: missense (38%), nonsense (22%), splicing (5%), small deletion/insertions (28%) and a large deletions (5%). Almost all the pathogenic variants are located in in exon 2, except for the one splicing variant and the one large deletion (Human Gene Mutation Database). The nonsense variant c.259C>T (p.Arg87*) was found in three unrelated TCS families. Non-penetrance was seen in one of the four families with POLR1D variants. Note that exon numbering differs from Dauwerse's publication (Dauwerse et al. 2011. PubMed ID: 21131976).

TCS3 is inherited in an autosomal recessive form and is caused by pathogenic variants in the POLR1C gene. To date, five unique causative variants have been identified in three unrelated index TCS patients. They are: 2 missense, one nonsense, and 2 small deletions (Dauwerse et al. 2011. PubMed ID: 21131976).

TCS type 4 is inherited in an autosomal dominant manner and is caused by missense variants in the POLR1B gene. At least three of the six reported causative variants occurred de novo (Sanchez et al. 2020. PubMed ID: 31649276).

Mandibulofacial Dysostosis, Guion-Almeida is inherited in an autosomal dominant manner and is caused by pathogenic variants in the EFTUD2 gene. To date, ~ 50 causative variants have been identified in patients with MFDGA. These causative variants are: missense (24%), nonsense (20%), splicing (14%), small deletion/insertions (27%), and large deletions (14%). The majority of the reported cases have a de novo heterozygous loss of function variant (Lines et al. 2012. PubMed ID: 22305528; Gordon et al. 2012. PubMed ID: 23188108; Need et al. 2012. PubMed ID: 22581936).

Miller syndrome is inherited in an autosomal recessive manner and is caused by pathogenic variants in the DHODH gene. To date, ~20 unique variants have been documented (Human Gene Mutation Database): missense (87%); nonsense (6%), and a small deletion (6%). No large deletions/insertions have been reported (Ng et al. 2010. PubMed ID: 19915526; Rainger et al. 2012. PubMed ID: 22692683).

SF3B4-related Acrofacial dysostosis, Nager type is inherited in an autosomal dominant manner. In a study of 14 families, at least five of the sporadic cases were de novo, suggesting complete penetrance (Petit et al. 2014. PubMed ID: 24003905). The SF3B4 protein is a component of the U2 pre-mRNA spliceosomal complex involving RNA-binding activity. To date, ~30 unique pathogenic variants have been documented (HGMD): missense (6%); nonsense (20%), splicing (13%), small deletion/insertion (61%). No large deletions/insertions have been reported (Bernier et al. 2012; Petit et al. 2014. PubMed ID: 24003905; Castori et al. 2014. PubMed ID: 25337072; HGMD). One SF3B4 de novo pathogenic variant was found in a patient affected with Rodriguez syndrome, a severe acrofacial dysostosis, phocomelia with pre- and post-axial limb defects, fibular agenesis, rib, and shoulder girdle anomalies (McPherson et al. 2014. PubMed ID: 24715698).

See individual gene summaries for more information about molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

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. PubMed ID: 22317976; Katsanis and Jabs. 2018. PubMed ID: 20301704).

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. 2011. PubMed ID: 21131976).

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. 2011. PubMed ID: 21131976).

A few de novo or inherited missense variants in the POLR1B gene were reported in patients with TCS (Sanchez et al. 2020. PubMed ID: 31649276).

Sequencing may detect up to 85% of disease causing pathogenic variants in clinically diagnosed Mandibulofacial Dysostosis, Guion-Almeida Type cases. Large deletion/insertions involving EFTUD2 cause ~15% of cases (Lines et al. 2012. PubMed ID: 22305528; Gordon et al. 2012. PubMed ID: 23188108; Need et al. 2012. PubMed ID: 22581936; Human Gene Mutation Database).

Rainger et al. identified compound heterozygous pathogenic variants in DHODH in three out of eight unrelated families with Miller syndrome (Rainger et al. 2012. PubMed ID: 22692683).

Bernier et al. identified 18 different heterozygous SF3B4 pathogenic variants in 20 (57%) of 35 families affected by Acrofacial dysostosis, Nager type (Bernier et al. 2012. PubMed ID: 22541558).

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 features suggestive of Treacher Collins syndrome/ Mandibulofacial Dysostosis/ Miller syndrome and Acrofacial dysostosis, Nager type.

Genes

Official Gene Symbol OMIM ID
DHODH 126064
EFTUD2 603892
POLR1B 602000
POLR1C 610060
POLR1D 613715
SF3B4 605593
TCOF1 606847
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Bernier et al. 2012. PubMed ID: 22541558
  • Beygo et al. 2012. PubMed ID: 22712005
  • Bowman et al. 2012. PubMed ID: 22317976
  • Castori et al. 2014. PubMed ID: 25337072
  • Chang and Steinbacher. 2012. PubMed ID: 23633935
  • Dauwerse et al. 2011. PubMed ID: 21131976
  • Dixon. 1996. PubMed ID: 8875242
  • Donnai et al. 1987. PubMed ID: 3612717
  • Gordon et al. 2012. PubMed ID: 23188108
  • Human Gene Mutation Database (Bio-base).
  • Katsanis and Jabs. 2018. PubMed ID: 20301704
  • Lines et al. 2012. PubMed ID: 22305528
  • McPherson et al. 2014. PubMed ID: 24715698
  • Need et al. 2012. PubMed ID: 22581936
  • Ng et al. 2010. PubMed ID: 19915526
  • Petit et al. 2014. PubMed ID: 24003905
  • Rainger et al. 2012. PubMed ID: 22692683
  • Sanchez et al. 2020. PubMed ID: 31649276
  • Schaefer et al. 2014. PubMed ID: 24603435
  • Trainor et al. 2009. PubMed ID: 19107148
  • Vincent et al. 2014. PubMed ID: 23695276
  • Wieczorek et al. 2009. PubMed ID: 19334086

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.

For Requisition Forms, visit our Forms page


Specimen Types

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