Fabry Disease via the GLA Gene

Fabry disease (OMIM 301500) is a lysosomal storage disorder due to deficiency in the lysosomal enzyme glycohydrolase alpha-galactosidase A (α-GAL A) (Brady et al. N Engl J Med 276:1163-1167, 1967). The enzymatic deficiency results in the progressive accumulation of globotriaosylceramide and related glycosphingolipids in the vascular endothelium, causing the disease manifestations. Fabry disease is inherited as an X-linked recessive trait, and female carriers may develop the disease. It is a clinically heterogeneous disease even among affected members of the same family (Banikazemi et al. 2012).

In male patients with Fabry disease, two forms are recognized: the classic and atypical forms. The classic form is characterized by onset during the first two decades of life and features including corneal and lenticular opacities, angiokeratoma (skin lesions), acroparesthesias (excruciating pain in the extremities), and hypohidrosis (decreased ability to sweat). In the atypical form, symptoms begin later in life and include left ventricular hypertrophy, arrhythmias, or cardiomyopathy. The classical features are not present in cases with the atypical form of the disease.

In female heterozygotes, clinical manifestations are largely determined by random X-inactivation (Dobrovolny et al. J Mol Med 83:647-654, 2005). Female heterozygotes may be asymptomatic throughout a normal life span or affected with variable severity. Fabry disease occurs in diverse ethnic groups throughout the world, with an estimate incidence of 1 in 60,000 males (Meikle et al. JAMA 281:249-254, 1999). In untreated patients, death results from renal failure, heart failure, or myocardial infarction.

Variants in the GLA gene are responsible for the α-GAL A enzyme deficiency and subsequent development of Fabry disease (Bernstein et al. J Clin Invest 83:1390-1399, 1989). More than 500 variants, distributed along the entire coding region of the gene have been detected in patients with Fabry disease. Most variants are unique to single families and include missense, nonsense, splicing, and small insertions/deletion variants. Partial or whole deletions of the GLA gene accounted for less than 0.05 % of all Fabry disease cases, and complex rearrangements have been detected in only three patients.

This test detects GLA variants in nearly 100% of males with Fabry disease (Mehta and Hughes, GeneReviews, 2008). The sensitivity of this test in female heterozygotes is currently not known.

This test provides full coverage of all coding exons of the GLA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.