Comorbid autosomal dominant LDLR- and collagen VI-related disorders

Objectives. Collagen 6-related Bethlem myopathy and LDLR-related familial hypercholesterolemia are presumed to be quite rare in the general population.
Case report. Here, we present the clinical findings from a 65-year-old man with comorbid Bethlem myopathy and familial hypercholesterolemia to highlight some important molecular diagnostic considerations and clinical management implications.

The heterogeneity of the genotype and phenotype spectrum of collagen 6-related disorders (COL6-RD) is an area of growing interests, yet cases of genetic comorbidities that may impact long-term management outcomes are lacking. Here, we present a 65-year-old male who was diagnosed with concurrent autosomal dominant COL6A3-RD and LDLR- related familial hypercholesterolemia. The patient underwent gene panel testing [comprehensive neuromuscular diseases and comprehensive lipidemia panel at Invitae laboratories (San Francisco CA, USA)] followed by exome sequencing at GeneDx laboratories [Gaithersburg, MD, USA] in the setting of persistently elevated creatine protein kinase levels [ranging from around 600 to > 1000 (IU/L)], muscle weakness, muscle spasm, myalgias, inguinal hernia, diaphragmatic hernia, hyperlipidemia, carotid artery stenosis, abdominal aortic ectasia, renal cyst, transient ischemic attack, chronic liver disease, cardiac conduction disorder, and hypersomnia.

The patient had no known personal history of contractures or gait abnormalities. His family history includes multiple 1^st degree relatives with hyperlipidemia, but he has no known family history of muscle diseases (Fig. 1A). The patient’s myopathic symptoms began at age 56. The genetic tests demonstrated COL6A3-RD [due to a heterozygous pathogenic variant, c.399del (p.Ala134Leufs*14)] and LDLR- related familial hypercholesterolemia [due to a heterozygous pathogenic variant, c.781T > A (p.Cys261Ser)]. COL6A3 [NM_004369.4] c.399del is a novel frameshift variant that creates a premature translational stop signal (p.Ala134Leufs*14), which is predicted to result in an absent or disrupted protein product. Haploinsufficiency of COL6A3 has been associated with COL6A3-RD, Bethlem myopathy ^1,2. COL6A3 c.399del (p.Ala134Leufs*14) fulfills the PVS1 (very strong), PM2 (moderate, applied at supporting level), pathogenicity criteria of the American College of Medial Genetics (ACMG) and the Association for Molecular Pathology (AMP) variant classification system ³, hence was classified as a pathogenic variant. LDLR [NM_000527.4] c.781T > A (p.Cys261Ser) variant fulfills the PS4 (strong), PM1, PM2,PM5, and PP3 (supporting) criteria of the ACMG/AMP variant stratification system, hence was classified as a pathogenic variant. The patient’s relatives were unavailable for family variant testing for the COL6A3 and LDLR variants. The concurrent germline presence of COL6A3 c.399del (p.Ala134Leufs*14) and LDLR c.781T > A (p.Cys261Ser) resulted in a composite neuromuscular phenotype with cardiometabolic and cerebrovascular consequences. CT of the abdomen showed scoliosis (Fig. 1B), anterocentral rectus femoris muscle atrophy (Fig. 1C) consistent with Bethlem myopathy ⁴, and atherosclerotic disease of the aorta and iliac arteries (Fig. 1D) in the context of LDLR-related hypercholesterolemia.

Although autosomal dominant COL6A3- related Bethlem myopathy is a relatively mild neuromuscular disorder, without significant cardiac and respiratory involvement ⁵, the cerebrovascular and cardiovascular consequences of comorbid LDLR-related hypercholesterolemia resulted in a more complex phenotype. Our observations suggest that providers should consider possibilities of comorbid genetic disorders in patients who have COL6A3- related disorders in a setting of severe cardiorespiratory and/or cerebrovascular diseases. On their own, LDLR- and COL6A3- related disorders are presumed to be quite rare in the general population, nevertheless the increasing application of genetic testing technologies in clinical settings may help shed light on the prevalence of the dual diagnosis.

Acknowledgements

The authors thank the patient whose participation made this project possible. The authors are grateful to the healthcare providers involved in the patient’s care.

Conflicts of Interest statement

The authors have no conflicts of interest to declare.

Funding

None.

Authors contribution

Conceptualization: M.A.O. Methodology: M.A.O., B.A.O. D.M., J.B.T., K.I.D., G.B., R.S.P., R.D., F.S. Data Analysis; M.A.O., B.A.O., D.M., J.B.T., K.I.D., G.B., R.S.P., R.D., F.S. Writing (original draft): B.A.O. Writing (reviewing and editing): M.A.O., B.A.O., D.M., J.B.T., K.I.D., G.B., R.S.P., R.D., F.S. Supervision: M.A.O. Guarantor: M.A.O.

Consent to participate

Informed consent was obtained from the patient for the study. Informed consent was obtained from the patient for publication.

History

Received: July 20, 2025

Accepted: Septermber 11, 2025

Figures and tables

Figure 1. (A) Pedigree showing multiple 1^st degree relatives with hyperlipidemia. Coronal CT image of the abdomen (B) shows dextroconvex lumbar scoliosis with associated multilevel degenerative disc disease. Axial CT image of the left thigh (C) shows anterocentral atrophy of the rectus femoris muscle (arrowhead) characteristic of Bethlem myopathy. Coronal CT maximum intensity projection (MIP) image (D) shows extensive atherosclerotic disease (arrows) involving the aorta and bilateral common iliac arteries.