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Gene-disease assertions not curated here (add link or write note): Did not curate AR Ullrich congenital muscular dystrophy; Invitae curated as strong in GenCC

Disease

Bethlem myopathy

Inheritance

Autosomal dominant

Prevalence

 

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

CLINGEN - NONE.

GenCC - Strong by both Ambry and Invitae (sufficient to skip clinical validity scoring; however, making notes below as I want to review gene further to document the clinical phenotype.

BabySeq - none

Clinical Validity Scoring Notes and points

Hicks 2014 PMID: 24334769

  • Two families (1 and 2) with Bethlem myopathy were found to have COL12A1 variants via WES. Family 1 - NM004370; c.G8357A: p.Gly2786Asp segregated in mother (1a) and daughter (proband, 1b). Family 2 NM004370c.C5893T:p.Arg1965Cys segregated in father (2a), and two sons (2b, 2C). Abnormal muscle biopsy in 1b and family 2 per fig 3, and showed dermal intracellular retention of collagen 12, collagen 12 labelling weaker at the fascia in patient 1a and 2a. 1 point each for variants (2 POINTS TOTAL), 3 total segs.

Zou 2014 PMID: 24334604

  • Family A is a recessive congenital myopathy family

  • Family B - Hypotonia, proximal joint contractures and distal joint hyperlaxity were noted during the first year of life. NM004370 c. 7167 T>C; NP004361 p. Ile2334Thr identified via candidate gene sequencing following haplotype analysis. immunocytochemical of dermal fibroblasts showed a reduction of collagen XII matrix in culture derived from patient B (Fig3b). Variant was de novo per the text, but I don’t see any evidence that parents were sequenced; however It does seem likely to be de novo based on the descriptions of family A where parents were tested (1.5 point)

  • Col12a1 -/- mice had decreased grip strength and decreased hindlimb splaying (indicating muscle weakness). Skeletal muscles from null mice showed decrease tetanic and specific force. 0.5 POINT MOUSE MODEL (downgrading since it is an AR model)

Punetha 2017 PMID: 27348394

  • COL12A1 c.8329G>C (p.Gly2777Arg) identified via targeted sequencing panel in a patient with profound hypotonia, joint laxity at birth, and a pregnancy complicated by oligohydramnios and intrauterine growth retardation. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein consistent w/ a dominant negative mutation. Absent in proband’s mother (father unavailable). 1 POINT

Coppens 2022 PMID: 35019233

  • Patient w/ fetal hypokinesia, severe neonatal weakness, hyperlaxity, high arched palate, retrognathia, club feet, pectus excavatum. Motor dleayed, muscle strength improved over time but hyperlaxity was very severe with recurrent joint dislocations. Trio exome identified in frame del exons 45-54 in COL12A1. 1.5 point.

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

unknown (proposed dominant negative in PMID: 27348394)

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Birth - adolescence (PMID: 24334769, 24334604)

Severity

 Options

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.

Clinical Features

Sources: 24334769, 24334604)

  • Proximal weakness,

  • Scapular winging

  • Joint hyperlaxity, hip dislocation

  • Scoliosis

  • Dysmorphic features

  • Generalized infantile hypotonia, torticollis, kyphosis

  • Contractures (fingers, elbows, knees)

  • Hypertrophic/atrophic scarring

  • May have myopathic/fibrosis, on muscle biopsy

PMID: 27348394

  • Scoliosis

  • Dysmorphic features (facial asymmetry with skull flattening, micrognathia, short nose, big dysplastic ears, high-arched palate, pectus excavatum and long slender fingers)

  • Delayed motor milestones.

  • Poor weight gain.

PMID: 35019233

  • Patient w/ fetal hypokinesia, severe neonatal weakness, hyperlaxity, high arched palate, retrognathia, club feet, pectus excavatum. Motor dleayed, muscle strength improved over time but hyperlaxity was very severe with recurrent joint dislocations.

HPO Terms

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

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

 Examples

- 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 COL12A1 gene is associated with autosomal dominant Bethlem myopathy, which is characterized by neonatal or infantile hypotonia, joint laxity, hip dyslocation, flexion finger contractures, delayed motor milestones, proximal weakness, scapular winging, and facial features such as micrognathia, short nose, dysplastic ears, and high arched alate. The onset is typically from birth or in childhood, and muscle strength tends to improve during teenage years (PMID: 24334769, 24334604, 27348394, 35019233). This gene is also associated with autosomal recessive Ullrich congenital myopathy, a severe autosomal recessive disorder characterized by joint hypermobility, proximal contractures, and muscle weakness precluding ambulation (PMID: 24334604).

Case ID, Curator name, Date, Jira ticket link

56752207081554, andrea oza, 06.11.2024

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