Caveolinopathy via the CAV3 Gene

The caveolinopathies are disorders of skeletal and cardiac muscle that include limb-girdle muscular dystrophy type 1C (LGMD1C; OMIM 607801), rippling muscle disease (RMD; OMIM 606072), hypertrophic cardiomyopathy (OMIM 192600), and long-QT syndrome 9 (LQT9; OMIM 611818). Remarkable variability in expression is known and any of the phenotypes may occur in different members of the same family (Bruno et al. GeneReviews, 2007). LGMD1C is characterized by mild-to-moderate proximal muscle weakness, calf hypertrophy, and positive Gower sign with onset in the first decade of life (Minetti et al. Nat Genet 18:365–368, 1998). Serum CK levels are elevated up to 25-fold above normal and muscle biopsies reveal a dystrophic pattern with increased numbers of central nuclei and increased connective tissue (eg., Fulizio et al. Hum Mutat 25:82-89, 2005). RMD is a non-dystrophic muscle disorder characterized by mechanically-induced muscle contractions (Betz et al. Nat Genet 28:218-219, 2001). Onset of symptoms occurs in childhood and includes painful muscle stiffness, weakness, cramping, percussion-induced muscle mounding, and muscle hypertrophy. Muscle biopsies reveal increases in fiber size variability, centrally located nuclei, and mild type-1 fiber predominance (Betz et al. 2001). A single case report of hypertrophic cardiomyopathy due to a CAV3 variant is known (Hayashi et al. Biochem Biophys Res Comm 313:178-184, 2004). CAV3 variants are also causative for long-QT syndrome via a gain of function increase in late sodium current (Vatta et al. Circulation 114:2104-2112, 2006). Other associations with CAV3 variants include hyperCKemia (Carbone et al. Neurology 54:1373–1376, 2000), sudden infant death syndrome (Cronk et al. Heart Rhythm 4:161-166, 2007), and distal myopathy (Tateyama et al. Neurology 58:323–325, 2002).

The caveolinopathies are most often inherited in an autosomal dominant mode with one parent of an affected child also affected. However, reports of recessive inheritance are also known (McNally et al. Hum Molec Genet 7:871-877, 1998; Kubisch et al. Ann Neurol 57:303-304, 2005; Muller et al. Neuromuscul Disord 16:432-436, 2006), though the health status of the carrier parents in these cases has not been well established. The same CAV3 variant can cause varied clinical and histological consequences between and within families.

Analytical sensitivity should be high as nearly all reported CAV3 variants are the type expected to be detected by sequencing of genomic DNA. Clinical sensitivity is difficult to predict because caveolinopathies are rare. Among a cohort of 663 patients who had a range of clinical phenotypes and were seen at an Italian neuromuscular disorders center, seven probands with caveolin deficient muscle biopsies and CAV3 variants were found (Fulizio et al. Hum Mutat 25:82-89, 2005). Among 905 unrelated long QT syndrome patients, four were found to have CAV3 variants (Vatta et al. Circulation 114:2104- 2112, 2006).

This test provides full coverage of all coding exons of the CAV3 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).