Inheritance

Autosomal dominant (With expansions in allele size in successive generations. Repeats 50-500 show paternal expansion bias, CTG >500 show maternal expansion bias. PMID: 35205411, 25712547)

Prevalence

 1:100,000 in some areas of Japan to 1:10,000 in Iceland, with an overall estimated worldwide prevalence of 1:20,000 [Theadom et al 2014].

Source: GeneReviews, NBK1165

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - no curations. GenCC - Invitae= strong, TGMI|G2P = definitive; BabySeq = Definitive (cites: PMIDs 1310900, 16285929, 23404338, 21623381, 9563950, 23263591)

Clinical Validity Scoring Notes and points

BabySeq PMID: 28079900, table S1. PMIDs: 1310900, 16285929, 23404338, 21623381, 9563950, 23263591

Clinical Validity Points Total

n/a; no points

Source: BabySeq

Clinical Validity Classification

Definitive

Source: BabySeq

Molecular Mechanism

Loss of function / Gain of function (PMID: 9563950, 23263591, 33269537) / Dominant Negative

Triplet-repeat expansion: CTG repeat in the 3’ UTR of DMPK

• Normal: 5-34

• Premutation: 35-49

• Pathogenic: >49

30588381, 1310900, 35205411, 28213156, 20301344, 25121518

Penetrance

(list source/PMID)

Penetrance is presumed full penetrance for pathogenic alleles.

Source: 28213156,

Age of Onset

(list source/PMID)

Dependent on repeat size. Congenital (750-1400); Pediatric (400-1100); Adult (250-750); Late onset 100-600

Source: 28213156, 25121518

Severity

MOderate to Severe

Clinical Features

Mild: Cataracts, myotonia, diabetes mellitus

Classic:

• Muscle: weakness (typically distal muscle weakness, handgrip myotonia, myotonic facies, dysarthria

• Cardiac: conduction defects, dilated cardiomyopathy

• Pulmonary: progressive impairment

• GI: Smooth muscle involvment → dysphagia, constipation, intestinal pseudoobstruction, diarrhea, gallstones

• Cognition/CNS: minot deficits, age-related cognitive decline, lower IQ, anxiety/depression, hypersomnia and sleep apnea. MRI may show mild cortical atrophy, white matter abnormalities.

• Nerve: Axonal peripheral myopathy

• Eye: cataracts

• Endocrine: hyperinsulinism, thyroid dysfunction, diabetes mellitus, calcium dysregulation, testicular atrophy

• Skin: Pilomatrixomata and epitheliomas (esp on scalp); alopecia/balding

Congenital: Infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adult.

Sources: 20301344

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

Pathogenic variants are triplet repeat expansions, see molecular mechanism section.

Curation Summary

The DMPK gene is associated with autosomal dominant myotonic dystrophy type 1 and is caused by a triplet repeat expansion in the 3' untranslated region. Severity and age of onset are linked to the length of the repeat expansion, with earlier and more severe features observed in individuals with longer repeats. Mild clinical features include cataracts and/or mild myotonia. Features observed in individuals with a classic presentation include muscle weakness, cardiac conduction defects and/or dilated cardiomyopathy, pulmonary involvement, cataracts, diabetes mellitus and other endocrine dysfunctions, and alopecia. Congenital myotonic dystrophy can present with the classic features as well as infantile hypotonia, intellectual disability, respiratory failure, and feeding difficulties (PMID: 25121518).

Case ID, Curator name, Date, Jira ticket link

https://broadinstitute.atlassian.net/browse/BCL-168 Andrea Oza, 8.30.2023