Download New genetic test for rare mutations that cause hypertrophic

New genetic test for rare mutations that cause hypertrophic cardiomyopathy
(HCM-Genomic scan)
Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease, characterized by
thickening of the heart muscle. Clinically, HCM is characterised by dyspnoea, palpitations,
arrhythmias and sudden death. In some cases it progresses to heart failure. There is, however,
great variation in the clinical picture even within the same family. The leading cause of HCM is
mutations in the genes which encode the protein components of the myocyte contractile unit, the
sarcomere, as well as genes which encode sarcomere-associated proteins. For many years, SSI has
offered an analysis package, "HCM study (R550)", which examined the 11 most frequently affected
genes for HCM-causing mutations. However, some of the referred patients do not have mutations
in these genes, consequently, SSI has developed a next-generation sequencing (NGS)-based
method for scanning an additional 16 genes which have been reported to cause HCM in rare cases.
Background
Genetic diagnosis of HCM is primarily of value if there are family members who may be
asymptomatic carriers. HCM develops with age, few have symptoms in childhood, but symptoms
may develop from adolescence. In families with a known disease-causing mutation, asymptomatic
carriers can be identified and members of the family not at risk of developing the HCM can also be
identified - from a clinical point of view, identifying non-affected family members is very
important. This allows that clinical follow-up will be given to the family members who have a real
genetic risk. The existing genetic test for HCM, SSI "HCM test (R550)", identifies a mutation in
approx. 50 - 60% of those examined. Thus, 40-50% of patients do not get a genetic diagnosis. Since
mutations in several genes that are not covered by the standard investigation can, in rare cases,
cause HCM, we have developed an NGS-based method for scanning 16 candidate genes, including
the gene encoding the large sarcomeric protein Titin. In HCM patients where standard
investigation of the frequently affected genes "HCM test (R550)" did not return a putative diseasecausing mutation now have an additional offer. In cases where disease-associated mutations have
been identified; family members can be offered cascade screening.
Indication
The test should be performed if "HCM test (R550)" has not led to the detection of mutations.
Danish and Swedish studies suggest that it is also indicated to examine children, as they may
develop fatal arrhythmias before ailment also manifests itself clinically.
Results and interpretation
Currently, the test covers screening of the coding regions of genes: ACTN2, ANKRD1, CRYAB, FHL1,
GLA, JPH2, KLF10, MYH6, MYLK2, MYOM1, MYOZ2, MYPN, NEXN, TNNC1, TTN and VCL. Genetic
reports will consist of a list of those identified variants which are estimated to be diseaseassociated. Since the experience with mutations in several of these genes is very modest, reports
may be inconclusive, but these cases will form the basis for further focused studies.
Specimen Collection and Submission
The laboratory prefers to receive 2 mL EDTA / full blood. Since a large concentration of DNA is
required, it is recommended not to send purified DNA. The sample must be submitted in a clearly
marked, properly sealed tube, placed in a sealed plastic bag and sent in a Styrofoam shipping box
with a cold pack. Do not freeze or heat the sample.
Requisition and prices
The study "HCM Genomic scan" and "Single Mutation Screening" for assessing known diseasecausing mutations in a family (cascade screening) may be performed.
Further information
Information and advice can also be obtained by contacting Dr. Michael Christiansen, Section of
Molecular Medicine, KBIG, tel: 3268 3657 or email: [email protected]
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