Clinical Guidance

COL6-RDs can be caused by either autosomal dominant or autosomal recessive pathogenic variants in COL6A1, COL6A2, and COL6A3 . Pathogenic variants associated with autosomal dominant inheritance in COL6A1, COL6A2, and COL6A3 typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes . Pathogenic variants associated with autosomal recessive inheritance are typically nonsense or frameshift variants . However, biallelic missense variants may be pathogenic when located near the C-terminal end of the TH domain, where they will be excluded from assembly .

COL6A1

Source: GeneReviews — "Collagen VI-Related Dystrophies"

A COL6-RD should be suspected in individuals with the following , , and findings.

Clinical Findings

Source: GeneReviews — "Collagen VI-Related Dystrophies"

Genetic testing for COL6A2 is available. Testing is considered confirmatory for diagnosis.

System/Concern | Evaluation | Comment

Musculoskeletal

| • Neuromuscular exam to evaluate degree distribution of muscle weakness its effects on mobility

• Exam of joint contractures, esp assessing for asymmetry of Achilles tendon contractures

• PT OT assessment

|

Pulmonary

| Baseline polysomnogram w/continuous CO2 monitoring | During childhood to assess ventilation during deep sleep

Pulmonary function tests in both upright (seated) supine (lying down) positions w/forced vital capacity monitored closely | Starting at age 5 yrs

Cardiology

| Eval w/cardiologist incl echocardiogram EKG | To evaluate for right-sided heart strain in those w/respiratory insufficiency who are not using NIV or have inadequate BiPAP pressures

Other

| Consultation w/clinical geneticist /or genetic counselor |

BiPAP = bilevel positive airway pressure; NIV = noninvasive ventilation; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "Collagen VI-Related Dystrophies"

UCMD / intermediate COL6-RD

• Respiratory function surveillance is of utmost importance in UCMD and intermediate COL6-RD, since unrecognized or underrecognized respiratory insufficiency is the leading cause of morbidity and mortality. PFTs should be performed in both the upright (seated) and supine (lying down) positions every six months to monitor the FVC.

Source: GeneReviews — "Collagen VI-Related Dystrophies"

Phenotype severity distribution: 8 always present features, 5 common features.