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

Typical: 28-56⁴; Range: 0-73⁵.

HPO Terms

–

Association

Mendelian

Locus

hg19 chr3:128891419-128891499

hg38 chr3:129172576-129172656

t2t chr3:131917482-131917557

Details

≤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/GGCT⁶. Many DM2 expansions include a downstream 3' (TCTG)n block after the main array. One cohort found this structure in 88% of DM2 patients⁷.

Mechanism

GoF

Aberrant splicing, RAN translation^8,9. Proposed pathogenisis contributions include nucleolar stress, autophagy dysregulation, and stress granule formation¹⁰.

Detection

Bidirectional RP-PCR and Southern blotting are commonly used for detection [@genereviews:NBK1466]. A downstream 3′ (TCTG)n block can cause false negative or unclear results, so TCTG targeted RP-PCR or long-read sequencing has been used to resolve these cases [@pmid:36018009; @pmid:41937177].

Year

2001¹¹

Location in Gene

Intron 1

Gene Strand

Alleles

Ref. Motif

CAGG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CAGG

Pathogenic (gene)

CCTG

Unknown (ref.)

CAGA

Unknown (gene)

CTGT

Interruption (ref.)

–

Interruption (gene)

–

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

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

Distinct cellular effects of myotonic dystrophy type 2 repeat-associated non-AUG tetrapeptides.

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 · 2026-05-18

pmid:42003432

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)

Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing.

Sophia B,Gibson, Nikhita,Damaraju, J Gus,Gustafson, Elsa V,Balton, Sirisak,Chanprasert, Ian A,Glass, Martha,Horike-Pyne, Runjun D,Kumar, Kathleen A,Leppig, Chris,Lundberg, Jane,Ranchalis, Elisabeth A,Rosenthal, Andrew K,Solomon, Andrew B,Stergachis, Mark,Wener, Gail P,Jarvik, Elizabeth E,Blue, Katrina M,Dipple, Harriet,Dashnow, Lea M,Starita, Danny E,Miller

medRxiv : the preprint server for health sciences · 2026-05-01

pmid:42094143

The novel (TCTG)

Federica,Centofanti, Virginia Veronica,Visconti, Maria Rosaria,D'Apice, Marco,Carlomagno, Simone,Maestri, Dario,Ciabini, Mario,Bengala, Enrica,Marchionni, Erica,Frezza, Roberto,Massa, Antonio,Petrucci, Francesca,Lupidi, Elena,Pegoraro, Gabriele,Siciliano, Matteo,Garibaldi, Paola,Origone, Massimo,Delledonne, Marzia,Rossato, Annalisa,Botta, Giuseppe,Novelli

Human genomics · 2026-04-05

pmid:41937177

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