DM2 CNBP

Myotonic dystrophy type 2 (MD2), also known as proximal myotonic myopathy, is a very rare genetic multi-system disorder of late childhood or adult-onset characterized by mild myotonia, muscle weakness, and rarely cardiac conduction disorders¹.

Prevalence

2.29 100,000

2.29/100,000²; population specific prevalence³. Most cases have European ancestry, but disease has been reported worldwide³.

Age of Onset Details

Typical: 28-56⁴; Range: 0-73⁵.

Locus

hg19

chr3:128891419-128891499

hg38

chr3:129172576-129172656

t2t

chr3:131917482-131917557

Details

Detailed overview of disease locus through 2024 by Rimoldi et al⁶. ≤30 uninterrupted CCTG repeats or 11-26 CCTG repeats with GCTC/TCTG interruptions are considered benign; 27-29 repeats with interruptions have currently unknown significance, ~30-~54 repeats are considered premutations, ~55-74 repeats are premutations with possible reduced penetrance, and >74 repeat alleles are considered pathogenic³. Penetrance is age-dependent and approaches 100%. Locus structure is (TG)n(TCTG)n(CCTG)n. CCTG expansion causes DM2 but the other repeat units are also variable. Interruptions include GCTG/TCTG/GGCT⁷. Many DM2 expansions include a downstream 3' (TCTG)n block after the main array. One cohort found this structure in 88% of DM2 patients⁸. Bidirectional RP-PCR and Southern blotting are used for detection [geneReviews:NBK1466]. A downstream 3′ (TCTG)n block can cause false negative or unclear standard 3′ CCTG-primed results, so TCTG targeted QP-PCR or long read sequencing can resolve these cases^9,.

Mechanism

GoF

Aberrant splicing, RAN translation^10,11. Proposed pathogenisis contributions include nucleolar stress, autophagy dysregulation, and stress granule formation¹².

Year

2001¹³

Location in Gene

Intron 1

Gene Strand

Alleles

Ref. Motif

CAGG

Pathogenic (ref.)

CAGG

Pathogenic (gene)

CCTG

Unknown (ref.)

CAGA

Unknown (gene)

CTGT

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0011266

Global Prevalence of Myotonic Dystrophy: An Updated Systematic Review and Meta-Analysis.

Qiao,Liao, Yihao,Zhang, Jian,He, Kun,Huang

Neuroepidemiology · 2022-04-28

pmid:35483324

Myotonic Dystrophy Type 2

Felix,Kleefeld, Hannes,Erdmann, Benedikt,Schoser

GeneReviews® · 1993-01-01

genereviews:NBK1466

Assessing the influence of age and gender on the phenotype of myotonic dystrophy type 2.

Federica,Montagnese, Stefania,Mondello, Stephan,Wenninger, Wolfram,Kress, Benedikt,Schoser

Journal of neurology · 2017-10-30

pmid:29086017

The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care.

Marie,De Antonio, Céline,Dogan, Ferroudja,Daidj, Bruno,Eymard, Jack,Puymirat, Jean,Mathieu, Cynthia,Gagnon, Sandrine,Katsahian, Dalil,Hamroun, Guillaume,Bassez

Orphanet journal of rare diseases · 2019-06-03

pmid:31159885

Myotonic dystrophies: an update on clinical features, molecular mechanisms, management, and gene therapy.

Martina,Rimoldi, Sabrina,Lucchiari, Serena,Pagliarani, Giovanni,Meola, Giacomo Pietro,Comi, Elena,Abati

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024-12-07

pmid:39643839

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

Updated Structure of

Martin,Wendlandt, Hannes,Erdmann, Simone,Rost, Morghan C,Lucas, Kerstin,Becker, Stephanie,Kleinle, Manuela,Timmer, Andrea,Bier, Gilbert,Wunderlich, Stephan,Wenninger, Maggie C,Walter, Teresa,Neuhann, Benedikt,Schoser, Elke,Holinski-Feder, Angela,Abicht

Neurology. Genetics · 2024-12-18

pmid:39703464

Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel.

Zhen Zhi,Tang, Viktor,Yarotskyy, Lan,Wei, Krzysztof,Sobczak, Masayuki,Nakamori, Katy,Eichinger, Richard T,Moxley, Robert T,Dirksen, Charles A,Thornton

Human molecular genetics · 2011-12-02

pmid:22140091

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

C L,Liquori, K,Ricker, M L,Moseley, J F,Jacobsen, W,Kress, S L,Naylor, J W,Day, L P,Ranum

Science (New York, N.Y.) · 2001-08-03

pmid:11486088

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Characterization of full-length

Massimiliano,Alfano, Luca,De Antoni, Federica,Centofanti, Virginia Veronica,Visconti, Simone,Maestri, Chiara,Degli Esposti, Roberto,Massa, Maria Rosaria,D'Apice, Giuseppe,Novelli, Massimo,Delledonne, Annalisa,Botta, Marzia,Rossato

eLife · 2022-08-26

pmid:36018009

Distinct cellular effects of myotonic dystrophy type 2 RAN tetrapeptides in Drosophila melanogaster.

Marta,Marzullo, Assia,De Simone, Marta,Terribili, Michela,Di Salvio, Degisew Yinur,Mengistu, Maria Patrizia,Somma, Rodrigo,D'Amico, Gianluca,Canettieri, Gianluca,Cestra, Laura,Ciapponi

Disease models & mechanisms · 2026-04-20

pmid:42003432

Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.

Stephanie J,Valberg, Zoë J,Williams, Elizabeth G,Ames, James R,Mickelson, Yvette S,Nout-Lomas, Gabriele,Landolt, Macarena,Sanz, Keri,Gardner

PloS one · 2026-01-29

pmid:41610137

Association of Non-Coding Repeat Expansions with Parkinson's Disease Risk: Evidence from a UK Biobank-Based Whole-Genome Sequencing Study.

Zhen,Hu, Qin-Qin,Yan, Jing-Jin,Wan, Yu,Fan, Jun,Liu

Movement disorders : official journal of the Movement Disorder Society · 2025-10-11

pmid:41074692

Optical genome mapping enables accurate testing of large repeat expansions.

Bart,van der Sanden, Kornelia,Neveling, Syukri,Shukor, Michael D,Gallagher, Joyce,Lee, Stephanie L,Burke, Maartje,Pennings, Ronald,van Beek, Michiel,Oorsprong, Ellen,Kater-Baats, Eveline,Kamping, Alide A,Tieleman, Nicol C,Voermans, Ingrid E,Scheffer, Jozef,Gecz, Mark A,Corbett, Lisenka E L M,Vissers, Andy Wing Chun,Pang, Alex,Hastie, Erik-Jan,Kamsteeg, Alexander,Hoischen

Genome research · 2025-04-14

pmid:40113266

High-resolution repeat structure analysis in myotonic dystrophy type 2 diagnostics using short-read whole genome sequencing.

Ingrid,Lojova, Marcel,Kucharik, Andrea,Zatkova, Andrej,Balaz, Zuzana,Pös, Eva Tothova,Tarova, Ludevit,Kadasi, Jaroslav,Budis, Tomas,Szemes, Jan,Radvanszky

Analytical biochemistry · 2025-02-01

pmid:39894140

Life expectancy and causes of death in patients with Myotonic Dystrophy Type 2.

Manon J,Damen, Otto G,Muilwijk, Tom Bg,Olde Dubbelink, Baziel Gm,van Engelen, Nicol C,Voermans, Alide A,Tieleman

Journal of neuromuscular diseases · 2024-11-01

pmid:39240646

Co-occurrence of

Wiktoria,Radziwonik-Frączyk, Ewelina,Elert-Dobkowska, Jolanta,Kubalska, Iwona,Stępniak, Marta,Lipowska, Anna,Potulska-Chromik, Anna,Sułek

Postepy psychiatrii neurologii · 2024-07-24

pmid:39119544

Effects of interrupting residues on DNA dumbbell structures formed by CCTG tetranucleotide repeats associated with myotonic dystrophy type 2.

Yingquan,Yang, Yang,Wang, Zhenzhen,Yan, Zhigang,Li, Pei,Guo

FEBS letters · 2024-06-25

pmid:38922834