Invitae Fabry Disease Test


Test description

This test analyzes α-galactosidase (GLA), the only known gene associated with Fabry disease. Testing should be considered for any individual with a clinical diagnosis of Fabry disease, a suspected clinical diagnosis of Fabry disease, or a family history of Fabry disease. On average, five family members are diagnosed with Fabry disease for every proband identified.

Molecular analysis of GLA is the only reliable way of diagnosing heterozygous females. Enzymatic studies of α-galactosidase in females who are obligate carriers or manifesting heterozygotes are often inconclusive due to X-inactivation. Heterozygous females may have α-galactosidase levels within the normal range.

Order test

Primary panel (1 gene)


GLA: Analysis includes the intronic variant NM_000169.2:c.IVS4+919G>A.

Fabry disease

Fabry disease is a rare, complex lysosomal storage disease with multisystemic involvement due to the progressive accumulation of globotriaosylceramide (GL-3) in the vascular endothelium. There is a phenotypic spectrum ranging from the severe, classic phenotype, to an attenuated phenotype, to atypical cardiac or renal variants.

Clinical subtypes:

Heterozygous females—Females heterozygous for a GLA pathogenic variant may remain clinically asymptomatic, present with an attenuated form of the disease, or manifest the full clinical spectrum of symptoms observed in males with classic Fabry disease.

Cardiac variant—This phenotype generally presents in males with greater than 1% enzymatic activity. Cardiomyopathy develops in the sixth to eighth decade of life and is characterized by left ventricular hypertrophy, hypertrophy of the interventricular septum, mitral valve insufficiency, and/or conduction abnormalities. Proteinuria may also be a feature, but end stage renal disease is typically absent.

Renal variant—This variant presents in males with greater than 1% enzymatic activity and has been diagnosed in Japanese patients with end stage renal disease and a prior diagnosis of chronic glomerulonephritis. Other symptoms of classic Fabry disease are generally absent, although moderate-to-severe left ventricular hypertrophy acroparesthesias and hypohidrosis have also been reported with the cardiac variant.

Symptoms include:

  • periodic severe pain crises in the extremities (acroparesthesias)
  • vascular cutaneous lesions (angiokeratomas), typically in the bathing-suit area
  • sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis)
  • exercise, heat, or cold intolerance
  • characteristic corneal and lenticular opacities (corneal whorls), observed by slit lamp examination
  • unexplained stroke (thrombosis, transient ischemic attacks [TIA], basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, frank cerebral hemorrhage)
  • cardiac disease (including mitral insufficiency, left ventricular enlargement, valvular involvement, and/or conduction involvement)
  • renal insufficiency
  • GI disturbances (episodic diarrhea, nausea, vomiting, bloating, cramping, abdominal pain, and/or intestinal malabsorption)

The classic phenotype in hemizygous males is the most commonly reported. Symptom onset generally occurs in childhood or adolescence, with the median reported age of 6 years in males and 9 years in females. The first detectable symptoms are usually acroparesthesias, angiokeratomas, hypohidrosis, and/or ocular findings. Cardiac and cerebrovascular disease is usually evident by middle age. Chronic kidney disease is present by the third decade of life and progresses to end stage renal disease (ESRD) by the fifth decade of life unless treated by chronic hemodialysis or renal transplant. Untreated Fabry disease causes a significantly reduced lifespan; the major causes of morbidity and mortality are renal failure, cardiovascular disease, and stroke. Heterozygous females may remain asymptomatic with a normal lifespan, have an attenuated form of the disease, or manifest all features of the severe, classic disease. Milder, non-classical variants include a cardiac form that has isolated cardiac symptoms developing in both males and females during sixth to eighth decade of life, and a renal form that leads to end stage renal disease occurring in the same time frame as males with the classic form of the disease. Symptoms such as milder left ventricular hypertrophy, acroparesthesias, and hypohidrosis have also been reported in cases with the renal variant.

More than 99% of patients with a clinical diagnosis of Fabry disease have an identifiable pathogenic mutation in GLA.

Fabry disease is inherited in an X-linked pattern.

Almost 100% of males and up to 80% of females with identified pathogenic variants develop signs and/or symptoms of the disease. Phenotypic expression of disease is highly variable both within the same family and among different families, and there may be subclinical expression in affected females.

Males with less than 1% enzyme activity typically present with classic Fabry disease, while those with greater than 1% may present with the cardiac or renal variant.

Females harboring a Fabry mutation may also present with symptoms of Fabry disease ranging from the classic disease to subclinical findings.

Fabry disease is panethnic, with no racial or ethnic predilection.

Birth prevalence is estimated at 1 in 30 000–35 000 births. Incidence in the general population has been estimated at 1 in 40,000 classically affected males. As milder cardiac and renal variants are being identified, and as Fabry disease newborn screening programs are being launched, these figures are being challenged. Recent newborn screening studies have shown that Fabry disease prevalence may be as high as 1 in 1,250 in certain populations.

Testing for Fabry disease should be considered in males and females with any or all of the following clinical symptoms:

  • a family history of Fabry disease
  • characteristic corneal verticillata (“whorls”) and lenticular opacities on slit lamp exam

In the absence of these two factors, testing is indicated in patients with at least two of the features below:

  • sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis)
  • vascular cutaneous lesions (angiokeratomas)—reddish-purple skin rash that is typically in the bathing-suit area
  • a personal and/or family history of kidney failure
  • a personal and/or family history of periodic severe pain crises, characteristically in the extremities (acroparesthesias)—often described as burning pain, particularly during fevers
  • a personal or family history of exercise, heat, or cold intolerance
  • an unexplained stroke
  • thrombosis, transient ischemic attacks (TIA), basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, and/or frank cerebral hemorrhage
  • cardiac disease, including mitral insufficiency, left ventricular enlargement, valvular involvement, and/or conduction involvement
  • unexplained left ventricular hypertrophy
  • renal insufficiency of unknown etiology

  1. Desnick, RJ, et al. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Kinzler KE, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Diseases. 8 ed. New York, NY: McGraw-Hill; 2001:3733-74. PMID: 11688379
  2. Eng CM, et al, Fabry disease: Guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006 Sep;8(9):539-48. PMID: 16980809
  3. Hopkin RJ, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 2008 Nov;64(5):550-5. PMID: 18596579
  4. Hwu WL, Chien YH,et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat. 2009 Oct;30(10):1397-405. PMID: 19621417
  5. Kikumoto, Y et al. The frequency of Fabry disease with the E66Q variant in the α-galactosidase A gene in Japanese dialysis patients: a case report and a literature review. 2012: Clin Nephrol. Sep;78(3):224-9. PMID: 22874111
  6. Laney DA, et al. Diagnosis of Fabry disease via analysis of family history. J Genet Couns. 2008 Feb;17(1):79-83. PMID: 18172746
  7. Laney, DA, et al. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. J Genet Couns. 2013 Oct;22(5):555-64. PMID: 23860966
  8. Mehta, A , Beck, M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 years of FOS. Oxford (United Kingdom): Oxford PharmaGenesis; 2006.
  9. Mehta, A, Hughes, DA. Fabry Disease. 2002 Aug 05. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301469
  10. Mehta, A, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. 2004: Eur J Clin Invest. 2004 Mar;34(3):236-42. PMID: 15025684
  11. Nakao S et al, Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. 2003: Kidney Int. 2003 Sep;64(3):801-7. PMID: 12911529
  12. Spada M, Pagliardini S, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006 Jul;79(1):31-40. PMID: 16773563

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GLA* NM_000169.2

GLA: Analysis includes the intronic variant NM_000169.2:c.IVS4+919G>A.