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Treacher Collins Syndrome
Genes: TCOF1; chr5q32  (TCS1)
POLR1D; chr13q12.2  (TCS2)
POLR1C; chr6p21.1  (TCS3)
Syndrome Information
Clinical Description:    Treacher Collins Syndrome (TCS) primarily affects craniofacial development.  The most common features include downward slanting palpebral fissures and lower lid coloboma; hypoplasia of malar bones and micrognathia; dysmorphic or hypoplastic external ears; and atresia of middle-ear ossicles sometimes resulting in conductive hearing loss.  Cleft palate and unilateral or bilateral choanal atresia are also possible.  
Inheritance Pattern:  Autosomal Dominant (TCOF1, POLR1D); Autosomal Recessive (POLR1C);
ariable expressivity and non-penetrance have been reported
Genotype-Phenotype Correlation:
None known; reported TCS caused by POLR1D and POLR1C mutations is clinically indistinguishable from that caused by TCOF1 mutations
Test Information
Test Method:  Bidirectional sequencing of the coding regions and intron-exon boundaries of

TCOF1 multiplex ligation-dependent probe amplification (MLPA) for deletions

(Must be ordered as separate tests - see Special Considerations below for suggested test strategy)

Clinical Utility: Identification of causative mutations in known or highly suspicious cases of Treacher Collins Syndrome; assessment of recurrence risk within the family; targeted diagnostic testing of relatives of proband with inconclusive clinical presentations; predictive prenatal testing when familial mutation is known.  
Clinical Sensitivity: TCOF1 sequence:  78-93% of patients with a clinical diagnosis of Treacher Collins Syndrome are expected top have a point mutation in TCOF1.

POLR1D sequence:  Approximately 7% of TCOF1 negative patients are expected to have POLR1D  mutations  

POLR1C sequence: Approximately 1% of TCOF1 negative patients are expected to have POLR1C mutations

TCOF1 MLPA: Approximately 2-4% of patients with Treacher Collins Syndrome will have a TCOF1 deletion.  Deletions comprise approximately 5% of TCOF1 mutations.   

Analytic Sensitivity:   

Sequence:  Greater than 97% for nucleotides analyzed.  All reports will indicate if a certain percentage of nucleotides were not called or were analyzed in a single direction.  

MLPA:  Estimated to be at least 95%.

Turn Around Time:   TCOF1 sequence:  3-4 weeks
POLR1D sequence: 3-4 weeks
POLR1C sequence: 3-4 weeks
TCOF1 MLPA: 4 weeks
Fee and CPT Codes:    TCOF1 sequence:  $2630 for routine testing

TCOF1 MLPA:  $429 for routine testing

POLR1D sequence: $470 for routine testing

POLR1C sequence:  $1086 for routine testing

Please contact the lab to arrange testing for known mutations on blood or prenatal samples. 

Special Considerations
TCOF1 point mutations account for the majority of TCS cases, and sequencing should be ordered as a first-tier test.  POLR1D and POLR1C are ordered ideally as second-tier tests after TCOF1POLR1D and POLR1C may be considered in sporadic cases.  POLR1D testing should be considered if there is a family history of Treacher Collins Syndrome in multiple generations. POLR1C testing should be considered in families with multiple affected siblings or with consanguinity.  These these tests may be ordered in any combination or order desired by the referrer.  Please add comments about test order or reflexing in the Notes/Clinical Information section of the requisition form (page 2) or speak with laboratory staff to arrange testing prior to shipping the sample. 
INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.

Helpful Links
Sample Requirements
Requisition and Billing forms
Clinical information on Treacher Collins Syndrome
Link to the General Test Information page for a discussion of the uses and limitations of genetic testing
Patient and Family Page for general resources on genetic testing.