Versions Compared

Version Old Version 1 New Version Current
Changes made by

Andrea Oza

Andrea Oza

Saved on

Key

  • This line was added.
  • This line was removed.
  • Formatting was changed.

...

Gene-disease assertions not curated here (add link or write note):

Disease

Myotonic dystrophy type 1

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

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 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?

  •  Rapid
  •  Full

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

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: BabySeq

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Penetrance is presumed full penetrance for pathogenic alleles.

Source: 28213156,

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

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

Source: 28213156, 25121518

Severity

Expand
titleOptions

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

Expand
titleExamples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

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

Jira Legacy
serverSystem JIRA
serverIdeee25142-2510-336f-918a-865682ebdf2e
keyBCL-168
Andrea Oza, 8.30.2023

...