Disease | Bethlem myopathy |
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Inheritance | Autosomal dominant |
Prevalence | |
Rapid or full curation? | |
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 | Expand |
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| title | Classifications (pts) |
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| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Source: |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| unknown (proposed dominant negative in PMID: 27348394) |
Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | Birth - adolescence (PMID: 24334769, 24334604) |
Severity | Expand |
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| 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. |
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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.
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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 | Expand |
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| - 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 myopathymuscular dystrophy, 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 |