TPM1-related Disorders: TPM1 Gene Sequencing

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Condition Description

Pathogenic variants in the TPM1 gene (15q22.2), inherited in an autosomal dominant manner, cause dilated cardiomyopathy and hypertrophic cardiomyopathy. 

Dilated Cardiomyopathy
Hereditary dilated cardiomyopathy (DCM) may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, depending on the gene involved.  DCM is characterized by left ventricular enlargement and reduced myocardial contraction force.  Typically, DCM presents with one of three features: heart failure, thromboembolic disease, or arrhythmias and/or conduction system disease.  Approximately 20-50% of idiopathic dilated cardiomyopathy (those cases not due to acquired causes) are thought to have a genetic cause.  

Hypertrophic Cardiomyopathy
Hereditary hypertrophic cardiomyopathy (HCM) is  characterized by left ventricular hypertrophy in the absence of a predisposing cardiac or cardiovascular condition.  The manifestation of HCM is extremely variable, even within the same family, and can range from asymptomatic to progressive heart failure.  Other features include syncope, presyncope, shortness of breath, chest pain, orthostasis, and palpitations.  The onset of HCM is usually during adolescence or young adulthood; however, it can range from infancy to much later in adult life.  

References:
  • GeneReviews
  • OMIM #191010:  TPM1 gene
  • OMIM #611878:  Dilated Cardiomyopathy 1Y
  • OMIM #115196:  Familial Hypertrophic Cardiomyopathy 3

Genes (1)

Indications

This test is indicated for:
 
  • Confirmation of a clinical diagnosis of TPM1-related disorders.
  • Carrier testing in adults with a family history of TPM1-related disorders.

Methodology

PCR amplification of 10 exons contained in the TPM1 gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Detection

Clinical Sensitivity: Unknown. Pathogenic variants in the promoter region, some pathogenic variants in the introns and other regulatory element pathogenic variants cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Analytical Sensitivity: ~99%

Specimen Requirements

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) or ACD (yellow top) tube: Infants (<2 years): 2-3 ml Children (>2 years): 3-5 ml Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.

Special Instructions

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of Emory Genetics Laboratory, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the TPM1 gene by CGH array is available for those individuals in whom sequence analysis is negative.
  • A cardiomyopathy panel and other single cardiac genes are available. 
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available only for known familial mutations to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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