Abstract
The clinical significance of the c.427G>A (p.A143T) variant in GLA is a topic of debate within the lysosomal storage disease community. A review of the literature and published case reports found the clinical impact of the variant to range from classic Fabry symptoms to healthy unaffected males with normal alpha- galactosidase enzyme levels, leaving clinicians unsure of how to manage these individuals. As the number of states testing for Fabry disease on their newborn screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the p.A143T variant affects those with this change. A self-response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals’ beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the p.A143T variant. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Beck, M. (2006). The Mainz severity score index (MSSI): Development and validation of a system for scoring the signs and symptoms of Fabry disease. Acta Paediatrica, 95(451), 43–46.
Brower, A., Hoffman, A. J., Thompson, B. H, & Watson, M. S. (2011). Utilization of the newborn screening translational research network to advance research and clinical applications in lysosomal storage disorders. 7th Annual WORLD Symposium 2011.
Corry, A., Feighery, C., Alderdice, D., Stewart, F., Walsh, M., & Dolan, O. M. (2011). A family with Fabry disease diagnosed by a single angiokeratoma. Dermatology Online Journal, 17(4), 5.
Desnick, R. J., Brady, R., Barranger, J., Collins, A. J., Germain, D. P., Goldman, M., et al. (2003). Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Annals of Internal Medicine, 138(4), 338–346.
Desnick, R. J., Doheny, D. O., Chen, B., Yu, C., Nazarenko, I., Lee, B., et al. (2015). Fabry disease: The alpha-galactosidase A (GLA) c. 427G>A (A143T) mutation, effect of the 5’-10C>T polymorphism. Molecular Genetics and Metabolism, 114(2), S37.
Eng, C. M., Ashley, G. A., Burgert, T. S., Enriquez, A. L., D’Souza, M., & Desnick, R. J. (1997). Fabry disease: Thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Molecular Medicine, 3(3), 174–182.
Green, R. C., Berg, J. S., Grody, W. W., Kaila, S. S., Korf, B. R., Martin, C. L., et al. (2013). ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine, 15(7), 565–574.
Hopkins, P. V., Campbell, C., Klug, T., Rogers, S., Raburn-Miller, J., & Kiesling, J. (2015). Lysosomal storage disorder screening implementation: Findings from the first six months of full population pilot testing in Missouri. The Journal of Pediatrics, 166(1), 172–177.
Howell, R. (2008). Letter from committee. Advisory committee on heritable disorders in newborns and children. Available at http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/nominatecondition/reviews/fabrydecision.pdf.
Karnilowicz, W. (2011). Identity and psychological ownership in chronic illness and disease state. European Journal of Cancer Care, 20(2), 276–282.
Kiesling, J. L. (2014) Missouri’s full population pilot screening for Fabry disease and the implications for families. Association of Public Health Laboratories. Available at http://www.aphl.org/conferences/proceedings/Documents/2014/NBS/29Kiesling.pdf .
Laney, D., Gruskin, D. J., Fernhoff, P. M., Cubells, J. F., Ousley, O. Y., Hipp, H., et al. (2010). Social-adaptive and psychosocial functioning of patients affected by Fabry disease. Journal of Inherited Metabolic Disease, 33(Supple3), S73–S81.
Laney, D., Bennett, R. L., Clarke, V., Fox, A., Hopkin, J., Johnson, J., et al. (2013). Fabry disease practice guidelines: Recommendations of the National Society of genetic counselors. Journal of Genetic Counseling, 22(5), 555–564.
Lavery, S. A., Aurell, R., Turner, C., Castellu, C., Veiga, A., Barri, P. N., et al. (2002). Preimplantation genetic diagnosis: patients’ experiences and attitudes. Human Reproduction, 17(9), 2464–2467.
Lenders, M., Weirdemann, F., Kurschat, C., Canaan-Kuhl, S., Duning, T., Stypmann, J., et al. (2016). Alpha- galactosidase A p. A143T, a non-Fabry disease- causing variant. Orphanet Journal of Rare Diseases, 11(1), 54.
Nance, C. S., Klein, C. J., Banikazemi, M., Dikman, S. H., Phelps, R. G., McArthur, J. C., et al. (2006). Later-onset Fabry disease: An adult variant presenting with the cramp-Fasiculation syndrome. Archives of Neurology, 63(3), 453–457.
National Society of Genetic Counselors. (2015). Position Statements: Prenatal Testing for Adult-Onset Conditions. Available at http://www.nsgc.org/p/bl/et/blogaid=259.
National Society of Genetic Counselors. (2017). Position Statements: Genetic Testing of Minors for Adult-Onset Conditions. Available at http://www.nsgc.org/p/bl/et/blogaid=860.
Niemann, M., Rolfs, A., Stork, S., Bijnens, B., Breunig, F., Beer, M., et al. (2014). Gene mutations versus clinically relevant phenotypes. Circulation: Cardiovascular Genetics, 7(1), 8–16.
Palanza, P. (2001). Animal models of anxiety and depression: How are females different? Neuroscience and Biobehavioral Reviews, 25(3), 219–233.
Rohman, P., Ramaswami, U., Mehta, A., & Hughes, D. A. (2015). Three significant milestones and a review of the A143T mutation within one family with Anderson-Fabry disease. Nephron Clinical Practice, 130, 91.
Sack, K. E. (2012). Taking away the diagnosis. Texas Heart Institute Journal, 39(1), 1.
Sharmirzadi, L., Chao, E. C., Palmaer, E., Parra, M. C., Tang, S., & Farwell Gonzalez, K. D. (2014). Patient decisions for disclosure of secondary findings among the first 200 individuals undergoing clinical diagnostic exome sequencing. Genetics in Medicine, 16(5), 395–399.
Shashi, V., McConkie-Rosell, A., Schoch, K., Kasturi, V., Rehder, C., Jiang, Y. H., et al. (2016). Practical considerations in the clinical application of whole-exome sequencing. Clinical Genetics, 89(2), 173–181.
Smid, B. E., Rombach, S. M., Aerts, J. M. F. G., Kuiper, S., Mirzaian, M., Overkleeft, H. S., et al. (2011). Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients. Orphanet Journal of Rare Diseases, 6, 69.
Spada, M., Pagliardini, S., Yasuda, M., Tukel, T., Thiagarajan, G., Sakuraba, H., et al. (2006). High incidence of later-onset Fabry disease revealed by newborn screening. The American Journal of Human Genetics, 79(1), 31–40.
Terryn, W., Vanholder, R., Hemelsoet, D., Leroy, B. P., Van Biesen, W., De Schoenmakere, G., et al. (2013). Questioning the pathogenic role of the GLA p.Ala143Thr “mutations” in Fabry disease: Implications for screening studies and ERT. JIMD Reports, 8, 101–108.
Turbitt, E., Halliday, J. L., Amor, D. J., & Metcalfe, S. A. (2015). Preferences for results from genomic microarrays: Comparing parents and health care providers. Clinical Genetics, 87, 21–29.
von der Lippe, C., Frich, J. C., Harris, A., & Solbraekke, K. N. (2016). Experiences of being heterozygous for Fabry disease: a qualitative study. Journal of Genetic Counseling, 25(5), 1085–1092.
Vos, J., Otten, W., van Asperen, C., Jansen, A., Menko, F., & Tibben, A. (2008). The Counsellees’ view of an unclassified variant in BRCA1/2: Recall, interpretation, and impact on life. Psycho-Oncology, 17(8), 822–830.
Wallis, Y., Payne, S., McAnulty, C., Bodmer, D., Sistermans, E., Robertson, K., et al. (2013). Practice guideline for the evaluation of pathogenicity and the reporting of sequence variants in clinical molecular genetics. Association for Clinical Genetic Science. http://www.acgs.uk.com/media/774853/evaluation_and_reporting_of_sequence_variants_bpgs_june_2013_-_finalpdf.pdf. Accessed 13 April 2007.
Wang, R. Y., Lelis, A. L., Mirocha, J., & Wilcox, W. R. (2007). Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genetics in Medicine, 9(1), 34–45.
Westerfield, L., Darilek, S., & van den Veyver, I. B. (2014). Counseling challenges with variants of uncertain significance and incidental findings in prenatal genetic screening and diagnosis. Journal of Clinical Medicine, 3(3), 1018–1032.
Wise, D., Wallace, H. F., & Jellinek, E. H. (1962). Angiokeratoma Corporis Diffusum. Oxford Journals Medicine New Series, 31(2), 177–212.
Acknowledgements
We would like to recognize all of the patients that participated in this research study. Their willingness to participate in research and share their experiences never ceases to amaze us. We would also like to recognize the entire staff of the Emory Lysosomal Storage Disease Center. The research was conducted during training at Emory University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Sarah Macklin and Elizabeth Smith declare that they have no conflicts of interest.
Dawn Laney consults for Genzyme and Shire, and is a study coordinator in clinical trials sponsored by Genzyme, Amicus, and Protalix. She has also received research funding from Alexion, Amicus, Genzyme, Pfizer, Retrophin, Shire, and Synageva. Grant funding to conduct this investigator initiated was provided through an educational grant from Genzyme, A Sanofi company. In addition, she is a co-founder of ThinkGenetic.com. These activities are monitored and are in compliance with the conflict of interest policies at Emory University School of Medicine.
Andrea Atherton is an employee and receives salary from Shire. Emily Lisi has received research funding from Sanofi Genzyme and Shire.
Human Studies and Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Our study was declared exempt from written and oral informed consent by the Emory Institutional Review Board. All patients were provided with an information page our contact information should they have questions about participation.
Animal Studies
This article does not contain any studies with animals performed by any of the authors.
Electronic supplementary material
Supplementary Table 1
(DOCX 22 kb)
Rights and permissions
About this article
Cite this article
Macklin, S., Laney, D., Lisi, E. et al. The Psychosocial Impact of Carrying a Debated Variant in the GLA Gene. J Genet Counsel 27, 217–224 (2018). https://doi.org/10.1007/s10897-017-0139-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10897-017-0139-y