TTN

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#SINGLE GENE TEST, DELETE IF USING PGENE PANEL above Test-Type : single_gene #single_gene, gene_panel, other. Used to filter display Gene : TTN, TITIN #Gene symbol, gene name Exon : 307 to 312, mRNA reference sequence GenBank NM_133378 OMIM_omim : 188840 #Only use fo single_gene tests

#NEEDED BY ALL TEST TYPES Diseases : Dialed Cardiomyopathy type 1G, Familial Hypertrophic Cardiomyopathy type 9 (CMH9), Muscular Limb-girdle Muscular Dystrophy type 2J (LGMD2J), Early-onset myopathy with fatal cardiomyopathy, Proximal myopathy with early respiratory muscle involvement, Tibial muscular dystrophy tardive (TMD or Udd Distal Myopathy) #disease 1, disease 2. for different names of same disease use OR CPTs : 83890 x1, 83898 x13, 83894 x1, 83891 x1, 83904 x26, 83912 x1

Mutations within the the C-terminus of Titin (six exons)cause limb girdle muscular dystrophy type 2J (LGMD2J 608807) and tibial muscular dystrophy (TMD 600334). LGMD2J is a severe, early onset disorder characterized by weakness of all proximal muscles. In the first reported cases weakness appeared in the first decade of life and progressed over the next 20 years to wheelchair confinement (Udd et al. Muscle and Nerve 14:1050- 1058, 1991). Patients with the other, less severe, clinical presentation showed onset of distal muscle weakness in lower limbs in the third or fourth decade of life. Progression was very slow without greater disability throughout their lifetime. Tibial muscle weakness and wasting are clinical landmarks for TMD (Udd et al. 1991). By studying segregation of the two clinical phenotypes within a large consanguineous pedigree, Udd (J Med Genet 29:383-389, 1992) demonstrated that both were likely caused by a mutation in the same gene. Subsequently, Hackman et al. (Amer J Hum Genet 71:492-500, 2002) found homozygosity for an insertion/deletion mutation in the terminal exon of TTN in severely affected family members, and heterozygosity for the same mutation in members affected with the milder, adult onset TMD phenotype. Homozygous mutations in other exons encoding the C-terminus have been found to result in a condition with severe, early onset myopathy and fatal cardiomyopathy (Carmignac et al. Ann Neurol 61:340-351, 2007).

For more thorough review, see GeneReviews on Udd Distal Myopathy and DMRV

LGMD2J is an autosomal recessive, and TMD is an autosomal dominant disease. The TTN gene (OMIM 188840) encodes titin, a large 3,700kDa protein of 2uM length that spans from the Z disc to M band of the myofiber sarcomere. An 11 base pair insertion/deletion mutation in exon 312 of TTN (the terminal exon) has been shown to cause both LGMD2J and TMD in the Finnish population. Missense, and truncating mutations in exons 311 and 312 have also been found to cause LGMD2J and TMD in patients from Finland, France, and Spain (Hackman et al 2002; Hackman et al. Neuromuscul Disord 18:922-928, 2008). Patients with truncating mutation in exon 311, which also contains calpain 3 binding domain, have a more severe and earlier onset form of TMD (Hackman et al. 2008). Titin-related cardiomyopathy (CMD1G; OMIM 604145) is most often caused by mutations spread throughout the TTN gene; however, two unrelated patients with severe myopathy and fatal cardiomyopathy occurring together have been reported with homozygous truncating mutations in exons 307 and 309 (Carmignac et al. 2007).

Patients with clinical picture consistent with a described disease, a family member of patient for carrier/heterozygous testing, or a member of a high risk population.

Mouth or buccal epithelial cells (call us for collection kit), or blood collected in standard Vacutainers of Purple/Lavender top (EDTA) or Yellow top (ACD). Other sources of DNA may be acceptable depending on quality and purity measures – please contact us before submitting such other specimens.

2-4 weeks in most cases. Expedited (STAT) testing is available for additional 25% charge, and results are available in 4-10 business days in most cases.

The huge sarcomere protein Titin (formerly connectin) is encoded by exons 2-312 of the TTN gene located at chromosomal band 2q31. Six exons at the C-terminus of TTN encode immunoglobulin and calpain-3 binding domains are associated with the sarcomeric M band. These exons (307 -312) are referred to as Mex1–Mex6 in the literature. Testing either for exons 311-312, or for exons 307-312 may be requested.

Genomic DNA is isolated from the sample. The coding exons, and 40-100 bp of adjacent noncoding regions, are amplified by PCR. Each exon and flanking non-coding (intron) bases are sequenced by automated capillary electrophoresis using dye-terminator sequencing method (labeled dideoxynucleotide triphosphates, ddNTPs). DNA segments are tested by forward and reverse sequence runs to obtain a consensus sequence and confirm variation or mutation results.

For institutional accounts using grant awards or restricted funds, we guarantee lowest contact/bulk testing rates. Our pricing is based on CPT codes reasonable and customary charges, which may change slightly from year to year. We strive towards providing the needed testing services to every patient in need regardless of cost. On a case by case basis, we can provide free or pro-bono testing upon proof of financial difficulty.