BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.
- MeSH
- kardiomyopatie * klasifikace vrozené genetika MeSH
- konektin genetika MeSH
- lidé MeSH
- nemoci svalů * klasifikace vrozené genetika MeSH
- směrnice pro lékařskou praxi jako téma normy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Genetic test results can have considerable importance for patients, their parents and more remote family members. Clinical therapy and surveillance, reproductive decisions and genetic diagnostics in family members, including prenatal diagnosis, are based on these results. The genetic test report should therefore provide a clear, concise, accurate, fully interpretative and authoritative answer to the clinical question. The need for harmonizing reporting practice of genetic tests has been recognised by the External Quality Assessment (EQA), providers and laboratories. The ESHG Genetic Services Quality Committee has produced reporting guidelines for the genetic disciplines (biochemical, cytogenetic and molecular genetic). These guidelines give assistance on report content, including the interpretation of results. Selected examples of genetic test reports for all three disciplines are provided in an annexe.
- MeSH
- cytogenetické vyšetření MeSH
- diagnostické techniky molekulární MeSH
- genetické poradenství MeSH
- genetické testování normy MeSH
- lidé MeSH
- prenatální diagnóza MeSH
- zajištění kvality zdravotní péče MeSH
- zveřejnění normy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- směrnice pro lékařskou praxi MeSH
- MeSH
- alely MeSH
- aromatasa genetika MeSH
- běloši genetika MeSH
- genetické markery MeSH
- genotyp MeSH
- lidé MeSH
- mikrosatelitní repetice genetika MeSH
- nemoci koronárních tepen etnologie genetika MeSH
- polymorfismus genetický MeSH
- steroid-17-alfa-hydroxylasa MeSH
- věk při počátku nemoci MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- MeSH
- diabetes mellitus 2. typu genetika MeSH
- hemochromatóza genetika MeSH
- lidé MeSH
- mutace MeSH
- nemoci koronárních tepen genetika MeSH
- průřezové studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
