Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary: 

The GLA gene (NM_000169.2), which contains 7 coding exons and is located on chromosome Xq22.1, encodes the alpha-galactosidase A protein. Pathogenic variants in this gene are known to cause Fabry disease, which is inherited in an X-linked fashion. Fabry disease is a rare X-linked lysosomal storage disorder characterized by reduced alpha-galactosidase A enzyme and a range of clinical severity and ages of onset.

Classic Fabry disease is more severe and is characterized by:

Features that typically present during childhood or early adolescence:
•    Acroparasthesia
•    Angiokeratomas
•    Abdominal pain
•    Fever
Additional features that develop over time:
•    Hypohidrosis
•    Cornea verticillate
•    Cerebrovascular risks
•    Gastrointestinal difficulties
•    Proteinuria with progressive renal insufficiency
•    Cardiac findings:
     o    Left ventricular hypertrophy
     o    Hypertrophic cardiomyopathy
     o    Arrhythmia
     o    Valvular involvement

Late-onset Fabry disease is less severe and presents in middle to later adulthood primarily with the typical Fabry-related cardiac findings, as well as variable renal findings.

Symptomatic heterozygous individuals generally present in adulthood with milder features; however, variable expressivity is observed, and those with skewed X-inactivation may show more severe symptoms and earlier onset.

Unique Considerations: 
•    There are FDA-approved treatments for patients with Fabry disease.
•    Loss of function has been reported as the mechanism of disease for Fabry disease.

Clinical Resources: 
•    Understanding Your Secondary Findings Result

Citations: 
•    Desnick RJ et al. Ann Intern Med, 2003 Feb;138:338-46. PMID: 12585833
•    Lukas J et al. Hum Mutat, 2016 Jan;37:43-51. PMID: 26415523
•    Fan Y et al. J Clin Med, 2021 May;10(10):2160. PMID: 34067605
•    Stamerra CA et al. Adv Pharmacol Pharm Sci, 2021 May;2021:5548445. PMID: 34095851
•    Izhar R et al. Genes (Basel), 2023 Dec;15(1):37. PMID: 38254927
•    Mehta A, et al. GeneReviews. 2002 Aug 5 [Updated 2024 Apr 11]. PMID: 20301469
 
Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here.