Apparent Germline Mosaicism in Autosomal Dominant Centronuclear Myopathy


Clinical Management

Poster Number: Virtual


Jordan Bontrager, MS, CGC, University of Rochester Medical Center, Emma Ciafaloni, MD, U of R School of Medicine and Dentistry Neurology, Bo Hoon Lee, MD, University of Rochester Medical Center, Debra Guntrum, NP, University of Rochester Medical Center

Centronuclear myopathies (CNMs) are a group of conditions characterized by skeletal muscle weakness and centrally located skeletal fiber nuclei on muscle biopsy. Onset of muscle weakness in patients with CNM can vary from shortly after birth to early adulthood, and disease course is typically slowly progressive over time. Several genes have been described in association with CNM, and disease inheritance varies depending on the underlying genetic cause.

DNM2-related centronuclear myopathy accounts for around 12% of CNM patients and is inherited in an autosomal dominant fashion. There is a large degree of clinical variability between patients, ranging from severe neonatal forms to mild adult-onset forms. Additionally, patients within the same family harboring the same genetic mutation can vary in their disease severity.

We present a case of two siblings (diagnosed at ages 8 and 7) with autosomal dominant DNM2-related CNM. Both siblings presented in early childhood with low tone, abnormal gait, proximal weakness, ptosis, bifacial weakness, and ophthalmoplegia. Muscle biopsy was consistent with CNM, and molecular testing confirmed the presence of a heterozygous pathogenic variant in the DNM2 gene (c.1565G>A, p.R522H). This variant was subsequently confirmed in the patient’s affected brother.

The patients’ mother reported a history of severe scoliosis. The father reported being slower than his peers as a child, but had no other symptoms or signs of myopathy. Targeted genetic analysis was performed, and both parents were negative for the c.1565G>A pathogenic variant.

This finding is suggestive of germline mosaicism, a phenomenon which, to our knowledge, has not been reported for dominant centronuclear myopathy. Patients should receive genetic counseling regarding the possibility of germline mosaicism when discussing recurrence risk. The prevalence of germline mosaicism in DNM2-related CNM is unknown, and warrants further research.