Centronuclear Myopathy-2, Autosomal Recessive via the BIN1 Gene

Autosomal recessive centronuclear myopathy (CNM2; OMIM 255200) has been found to be caused by mutations in the BIN1 gene (Nicot et al. Nature Genet 39:1134-1139, 2007).  Clinical and histological features of CNM2 include proximal muscle weakness and centrally placed nuclei with onset of weakness normally from birth to childhood (Nicot et al. Nature Genet 39:1134-1139, 2007).  Progression of muscle weakness appears to be slow.  Mild to severe contractures present at birth have been noted in one family.  Claeys et al. (Neurology 74:519-521, 2010) reported a CNM2 patient who had difficulty running and climbing stairs since childhood and first walked at age 3.5 years.  At 11 years of age diffuse muscle atrophy and progressive muscle weakness was noted in this patient.  Later, he was described as having scapular winging, hyperlordosis, a waddling gait, and Gower’s sign.  Weakness was prominent in proximal and distal muscles of all four limbs.  The patient was also described as being mildly dysmorphic with an elongated face, high-arched palate, and retrognathia.  The feet were high-arched and clubbed.  Evaluation of a muscle biopsy revealed centrally placed nuclei.  Unlike the patients described by Nicot et al. (Nature Genet 39:1134-1139, 2007), this patient had mild mental retardation.  An earlier report by Wallgren-Pettersson et al. (J Med Genet 32:673-679, 1995) noted that at least 12 families (21 patients) were known with centronuclear myopathy and with pedigrees compatible with autosomal recessive inheritance.  Onset of weakness in these patients varied from infancy (6 patients) to early childhood (7 patients) to ages 8 through 30 years (8 patients).  Muscle weakness was typically proximally.  Other clinical findings among these patients included ophthalmoplegia, ptosis, facial weakness, and feeding difficulties.

Centronuclear myopathy is a genetically heterogeneous disorder.  One X-linked form and several autosomal dominant forms are known.  BIN1-related centronuclear myopathy is inherited as an autosomal recessive disorder.  Missense and nonsense mutations and are the only forms of pathogenic gene variants reported to date.  The reported mutations are believed to disrupt interaction of the BIN1 protein with dynamin 2, encoded by DNM2 (Nicot et al. Nature Genet 39:1134-1139, 2007).  BIN1 mRNA in skeletal muscle from patients with myotonic dystrophy has been shown to be affected by sequestration of the splicing regulator MBNL1 (Fugier et al. Nature Med 17:720-725, 2011).

Analytical sensitivity may be high because all BIN1 mutations reported to date will be detectable by direct sequencing of genomic DNA. Clinical sensitivity is problematic to predict due to genetic heterogeneity of this disorder. From a cohort of 55 patients with histologically-diagnosed centronuclear myopathy, and with suspected autosomal recessive inheritance, three unrelated patients from three consanguineous families with BIN1 causative mutations were found (Nicot et al. Nature Genet 39:1134-1139, 2007).

This test provides full coverage of all coding exons of the BIN1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).