Fabry Disease

Fabry Disease

Massive parallel sequencing method after amplification of GLA gene: this is the study of choice upon clinical suspicion of Fabry disease.

It is performed through NGS, by the method of amplification of the GLA gene. It includes all exons and non-coding regions (UTRs, introns, and adjacent regions). It allows the evaluation of possible structural variants and copy-number variation (CNVs), which increases its diagnostic yield with respect to the traditional Sanger method technique.

Informed consent

Hypertrophic cardiomyopathy panel:
Fabry disease is one of the main phenocopies of hypertrophic cardiomyopathy and patients are usually referred to doctors with this diagnosis. In case the suspicion of Fabry disease is not high, or if there are data of cardiac involvement not explained by this disease (pattern of hypertrophy not suggesting Fabry, hypertrophy at an early age or without involvement of other organs, etc.), we recommend starting the evaluation by any of the hypertrophic cardiomyopathy panels.

[18 genes panel]: our basic HCM panel is indicated as a first diagnostic approach upon clinical suspicion of HCM. It includes the 9 main sarcomeric genes associated with the disease and also contains 9 disease-associated genes whose clinical presentation can be indistinguishable from classic HCM (phenocopies), including GLA gene associated with Fabry disease.

[118 genes panel]: it includes both the main sarcomeric genes and all phenocopies of the disease, as well as secondary and candidate genes gathered in a systematic literature review. It is indicated when:
– The basic panel study is negative and there is a clear HCM phenotype, since this panel improves diagnostic yield.
– In case severe phenotypes or phenotypes associated with syndromes and other rare genetic diseases are detected.
– If an exhaustive genetic study of this pathology is intended, since this is the most complete panel for HCM in the market.

Cardiomyopathy global panel [204 genes]: this panel is aimed at the diagnosis of cases presenting some degree of myocardial involvement, but where the phenotype is not completely clear or there are some diagnostic uncertainties. It should also be considered when there is overlapping between phenotypes either in the patient or in the family, which is not infrequent in clinical practice. It is useful since:
– The genetic study allows confirming the clinical suspicion and is also an important tool for differential diagnosis of the disease.
– Proper and correct diagnosis of the disease allows for risk stratification.
– When a pathogenic mutation is detected, it can be used as a predictive test. It is useful for genetic counseling, since it allows detecting carriers at risk who should undergo appropriate clinical monitoring.

Study requisition form
Informed consent

Cardiovascular diseases global panel [405 genes]: this panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases as well as genes associated with increased global/general cardiovascular risk.

It covers a group of heterogeneous diseases, and genetic testing allows for the differential diagnosis between them. It is also useful when a multigenic etiology is suspected.

It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.

As for research, it is an attractive alternative to the exomes because it includes both genes with proven pathogenicity and candidate genes. The study ensures maximum yield with adequate coverages (which allows for assessing structural variants, such as large deletions and duplications).

Study requisition form
Informed consent

This is the study of choice upon clinical suspicion of Fabry disease.

It is performed through NGS, by the method of amplification of the GLA gene. It includes all exons and non-coding regions (UTRs, introns, and adjacent regions). It allows the evaluation of possible structural variants and copy-number variation (CNVs), which increases its diagnostic yield with respect to the traditional Sanger method technique.

Informed consent

Fabry disease is one of the main phenocopies of hypertrophic cardiomyopathy and patients are usually referred to doctors with this diagnosis. In case the suspicion of Fabry disease is not high, or if there are data of cardiac involvement not explained by this disease (pattern of hypertrophy not suggesting Fabry, hypertrophy at an early age or without involvement of other organs, etc.), we recommend starting the evaluation by any of the hypertrophic cardiomyopathy panels.

[18 genes panel]: our basic HCM panel is indicated as a first diagnostic approach upon clinical suspicion of HCM. It includes the 9 main sarcomeric genes associated with the disease and also contains 9 disease-associated genes whose clinical presentation can be indistinguishable from classic HCM (phenocopies), including GLA gene associated with Fabry disease.

[118 genes panel]: it includes both the main sarcomeric genes and all phenocopies of the disease, as well as secondary and candidate genes gathered in a systematic literature review. It is indicated when:
– The basic panel study is negative and there is a clear HCM phenotype, since this panel improves diagnostic yield.
– In case severe phenotypes or phenotypes associated with syndromes and other rare genetic diseases are detected.
– If an exhaustive genetic study of this pathology is intended, since this is the most complete panel for HCM in the market.

Cardiomyopathy global panel [204 genes]: this panel is aimed at the diagnosis of cases presenting some degree of myocardial involvement, but where the phenotype is not completely clear or there are some diagnostic uncertainties. It should also be considered when there is overlapping between phenotypes either in the patient or in the family, which is not infrequent in clinical practice. It is useful since:

– The genetic study allows confirming the clinical suspicion and is also an important tool for differential diagnosis of the disease.

– Proper and correct diagnosis of the disease allows for risk stratification.

– When a pathogenic mutation is detected, it can be used as a predictive test. It is useful for genetic counseling, since it allows detecting carriers at risk who should undergo appropriate clinical monitoring.

Study requisition form
Informed consent

This panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases as well as genes associated with increased global/general cardiovascular risk.

It covers a group of heterogeneous diseases, and genetic testing allows for the differential diagnosis between them. It is also useful when a multigenic etiology is suspected.

It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.

As for research, it is an attractive alternative to the exomes because it includes both genes with proven pathogenicity and candidate genes. The study ensures maximum yield with adequate coverages (which allows for assessing structural variants, such as large deletions and duplications).

Study requisition form
Informed consent
Nota genes
NOTES ON GENES
-> Priority genes: Genes where there is sufficient evidence (clinical and functional) to consider them as associated with the disease; they are included in clinical practice guidelines. -> Secondary genes: Genes related to the disease but with a lower level of evidence
or constituting sporadic cases. -> * Candidate genes: Without sufficient evidence in humans but potentially associated with the disease.
  • Subjects under suspicion or clinical diagnosis of Fabry disease.
    • Children and adolescents: Acute or chronic limb pain unresponsive to the usual analgesics (acroparesthesias), recurring fever of unknown origin, intolerance to heat, cold or exercise, chronic intestinal disorders of uncertain origin, diffuse angiokeratomas, hipohydrosis, proteinuria, growth retardation, corneal opacities (“cornea verticillata”).
    • Adults: Persistence of the above-mentioned symptoms, renal insufficiency of uncertain origin, left ventricular hypertrophy (hypertrophic cardiomyopathy), dyspnea, low tolerance to exercise, angina, thoracic pain, palpitations, arrhythmia, early cerebrovascular disease, loss of hearing and tinnitus.
  • Familial study: Search for a mutation previously identified in a proband (families of patients with Fabry disease in which a mutation has been previously identified).
  • Biegstraaten M, Arngrímsson R, Barbey F et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015 Mar 27;10:36.
  • Smid BE, van der Tol L, Cecchi F et al. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. Int J Cardiol. 2014 Dec 15;177(2):400-8.
  • Laney DA, Bennett RL, Clarke V et al. Fox A, Hopkin RJ, Johnson J, O’Rourke E, Sims K, Walter G. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors.J Genet Couns. 2013 Oct;22(5):555-64.
  • Gal A, Beck M, Winchester B. Clinical utility gene card for: Fabry disease. Eur J Hum Genet. 2012 Feb;20(2).

Disease-causing mutations are usually “point mutations”, approximately in 70% of cases, but small or large rearrangements have been described in up to 30% of cases.

Using NGS (which allows for the detection of possible deletions), the probability of detecting a positive genetic study when the disease is well characterized clinically is close to 100%.

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