ACMG TECHNICAL STANDARD: Myotonic dystrophy type 1 (DM1) testing, 2024 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG); April 2024
Genet Med. 2024 Jun 3:101145. doi: 10.1016/j.gim.2024.101145. PMID: 38836869.
The American College of Medical Genetics’ (ACMG) Technical standards are educational resources for clinical laboratory geneticists. This DM1 guideline updates the standards for myotonic dystrophy type 1 (DM1) originally published in 2009 and reaffirmed in 2015.
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The current revision:
- Updates the methodology section to include triplet repeat-primed polymerase chain reaction (PCR).
- Discusses the use of next-generation sequencing (NGS) and its technological limitations for detection of myotonic dystrophy protein kinase (DMPK) CTG expansions.
- Adds a section on Human Genome Variation Society (HGVS) nomenclature in accordance with current technical standards.
- Discusses the clinical utility of CCG and other interruptions within the DMPK CTG expansion.
This document is designed for genetic testing professionals and is not intended as a clinical practice guideline. The guideline summarizes:
- DM1 is caused by expansion of CTG repeats in the 3′ UTR of DMPK.
- Reduced penetrance and variable expressivity exist within the disorder, largely due to meiotic and mitotic instability of CTG repeats, and genetic anticipation.
- Variant repeats with interruptions can affect the ability to accurately detect abnormal alleles and the phenotypic consequence of fully-variable alleles with interruptions remains uncertain.
- These technical standards serve as a guide for clinical DM1 testing that should be applied to any methodology used.
- Short- read NGS in its current state cannot reliably detect expanded DMPK alleles and is not recommended at this time. Long-read sequencing can detect expanded DMPK alleles and mosaic alleles; however, it is not routinely used in clinical laboratories for detection of expanded repeats.
- With advances in TP- PCR, NGS, and other technologies, the approach to testing for DM1 is likely to change as technologies become more advanced in the detection of repeat expansions in DMPK.