The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease

Dominique P Germain^{1

2

3

4}, Sergey Moiseev⁵, Fernando Suárez-Obando⁶, Faisal Al Ismaili⁷, Huda Al Khawaja⁸, Gheona Altarescu⁹, Fellype C Barreto¹⁰, Farid Haddoum¹¹, Fatemeh Hadipour¹², Irina Maksimova¹³, Mirelle Kramis¹⁴, Sheela Nampoothiri¹⁵, Khanh Ngoc Nguyen¹⁶, Dau-Ming Niu^{17

18}, Juan Politei¹⁹, Long-Sun Ro²⁰, Dung Vu Chi¹⁶, Nan Chen²¹, Sergey Kutsev²²

Affiliations

¹ French Referral Center for Fabry disease, Division of Medical Genetics, University of Versailles, Montigny, France.
² First Faculty of Medicine, Charles University, Prague, Czech Republic.
³ Faculty of Medicine, University of Puthisastra, Phnom Penh, Cambodia.
⁴ MetabERN Center for Rare Diseases, APHP - Paris Saclay University, Paris, France.
⁵ Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia.
⁶ Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, and Servicio de Genética, Hospital Universitario San Ignacio, Bogotá, Colombia.
⁷ Nephrology Department, The Royal Hospital, Muscat, Oman.
⁸ MCH Hospital, Al-Hassa, Saudi Arabia.
⁹ Genetic Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
¹⁰ Service of Nephrology, Department of Internal Medicine, Federal University of Paraná, Curitiba, Brazil.
¹¹ Centre Hospitalo-Universitaire Mustapha, Algiers, Algeria.
¹² Medical Genetics Department, Atieh Hospital, Tehran, Iran.
¹³ Sanofi, Moscow, Russia.
¹⁴ Hospital Español, México City, Mexico.
¹⁵ Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kochi, India.
¹⁶ Center for Rare Diseases and Newborn Screening, Vietnam National Children's Hospital, Hanoi, Vietnam.
¹⁷ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁸ Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁹ Neurology Department, Laboratorio Neuroquímica Dr Néstor Chamoles Buenos Aires, Buenos Aires, Argentina.
²⁰ Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Taoyuan, Taiwan.
²¹ Department of Nephrology, Institute of Nephrology, Ruijin Hospital, The Medical School of Shanghai Jiao Tong University, Shanghai, China.
²² Research Centre for Medical Genetics, Moscow, Russia.

PMID: 33835733
PMCID: PMC8172211
DOI: 10.1002/mgg3.1666

Review

The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease

Dominique P Germain et al. Mol Genet Genomic Med. 2021 May.

. 2021 May;9(5):e1666.

doi: 10.1002/mgg3.1666. Epub 2021 Apr 9.

Authors

Affiliations

¹ French Referral Center for Fabry disease, Division of Medical Genetics, University of Versailles, Montigny, France.
² First Faculty of Medicine, Charles University, Prague, Czech Republic.
³ Faculty of Medicine, University of Puthisastra, Phnom Penh, Cambodia.
⁴ MetabERN Center for Rare Diseases, APHP - Paris Saclay University, Paris, France.
⁵ Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia.
⁶ Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, and Servicio de Genética, Hospital Universitario San Ignacio, Bogotá, Colombia.
⁷ Nephrology Department, The Royal Hospital, Muscat, Oman.
⁸ MCH Hospital, Al-Hassa, Saudi Arabia.
⁹ Genetic Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
¹⁰ Service of Nephrology, Department of Internal Medicine, Federal University of Paraná, Curitiba, Brazil.
¹¹ Centre Hospitalo-Universitaire Mustapha, Algiers, Algeria.
¹² Medical Genetics Department, Atieh Hospital, Tehran, Iran.
¹³ Sanofi, Moscow, Russia.
¹⁴ Hospital Español, México City, Mexico.
¹⁵ Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kochi, India.
¹⁶ Center for Rare Diseases and Newborn Screening, Vietnam National Children's Hospital, Hanoi, Vietnam.
¹⁷ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁸ Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁹ Neurology Department, Laboratorio Neuroquímica Dr Néstor Chamoles Buenos Aires, Buenos Aires, Argentina.
²⁰ Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Taoyuan, Taiwan.
²¹ Department of Nephrology, Institute of Nephrology, Ruijin Hospital, The Medical School of Shanghai Jiao Tong University, Shanghai, China.
²² Research Centre for Medical Genetics, Moscow, Russia.

PMID: 33835733
PMCID: PMC8172211
DOI: 10.1002/mgg3.1666

Abstract

Background: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise.

Methods: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries.

Results: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists.

Conclusion: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases.

Keywords: Fabry disease; at-risk populations screening; cascade genotyping; early diagnosis; family genetic testing; pedigree drawing; rare disease.

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Conflict of interest statement

D.P. Germain has received honoraria and consulting fees from Amicus Therapeutics, Sanofi Genzyme, and Takeda. S. Moiseev has received travel grants and/or fees for participation in advisory boards from Sanofi Genzyme and Takeda. G. Altarescu has received speaker honoraria from Amicus Therapeutics, Sanofi Genzyme, and Takeda. F.C. Barreto has received speaker honoraria from Sanofi Genzyme. I. Maksimova is an employee of Sanofi Genzyme. M. Kramis has received honoraria as scientific advisor and speaker from Sanofi Genzyme. S. Nampoothiri has received honoraria for travel and attending advisory boards from Sanofi Genzyme. D‐M. Niu has received research funding from Sanofi Genzyme and Takeda. J. Politei has received honoraria from Amicus Therapeutics, Sanofi Genzyme, and Takeda and consulting fees from Sanofi Genzyme and Takeda. S. Kutsev has received honoraria from Sanofi Genzyme. F. Suárez‐Obando, F. Al Ismaili, F. Haddoum, L‐S. Ro, and N. Chen have received honoraria for travel and advisory board attendance from Sanofi Genzyme. H. Al Khawaja, F. Hadipour, K.N. Nguyen, and D. Vu Chi declare no conflicts of interest.

Figures

**FIGURE 1**
PRISMA flow chart of the literature analysis on family screening in Fabry disease

**FIGURE 2**
Large French pedigree highlighting the need for exhaustive pedigree drawing and cascade genotyping

See this image and copyright information in PMC

References

1. Adalsteinsdottir, B. , Palsson, R. , Desnick, R. J. , Gardarsdottir, M. , Teekakirikul, P. , Maron, M. , Appelbaum, E. , Neisius, U. , Maron, B. J. , Burke, M. A. , Chen, B. , Pagant, S. , Madsen, C. V. , Danielsen, R. , Arngrimsson, R. , Feldt‐Rasmussen, U. , Seidman, J. G. , Seidman, C. E. , & Gunnarsson, G. T. (2017). Fabry disease in families with hypertrophic cardiomyopathy: Clinical manifestations in the classic and later‐onset phenotypes. Circulation. Cardiovascular Genetics, 10, e001639. 10.1161/CIRCGENETICS.116.001639 - DOI - PubMed
1. Auray‐Blais, C. , Blais, C. M. , Ramaswami, U. , Boutin, M. , Germain, D. P. , Dyack, S. , Bodamer, O. , Pintos‐Morell, G. , Clarke, J. T. , Bichet, D. G. , Warnock, D. G. , Echevarria, L. , West, M. L. , & Lavoie, P. (2015). Urinary biomarker investigation in children with Fabry disease using tandem mass spectrometry. Clinica Chimica Acta, 438, 195–204. 10.1016/j.cca.2014.08.002 - DOI - PubMed
1. Azevedo, O. , Gal, A. , Faria, R. , Gaspar, P. , Miltenberger‐Miltenyi, G. , Gago, M. F. , Dias, F. , Martins, A. , Rodrigues, J. , Reimão, P. , Pereira, O. , Simões, S. , Lopes, E. , Guimarães, M. J. , Sousa, N. , & Cunha, D. (2020). Founder effect of Fabry disease due to p. F113L mutation: Clinical profile of a late‐onset phenotype. Molecular Genetics and Metabolism, 129, 150–160. 10.1016/j.ymgme.2019.07.012 - DOI - PubMed
1. Barman, H. A. , Özcan, S. , Atıcı, A. , Özgökçe, C. , Öztürk, A. , Kafalı, A. E. , Çakar, N. E. , Tavşanlı, M. E. , Küçük, M. , Şahin, I. , & Okuyan, E. (2020). Ratio of Fabry disease in patients with idiopathic left ventricular hypertrophy: A single‐center study in Turkey. Anatolian Journal of Cardiology, 23, 79–85. 10.14744/AnatolJCardiol.2019.84782 - DOI - PMC - PubMed
1. Boutouyrie, P. , Laurent, S. , Laloux, B. , Lidove, O. , Grunfeld, J. P. , & Germain, D. P. (2002). Arterial remodelling in Fabry disease. Acta Paediatrica, 91, 62–66. 10.1111/j.1651-2227.2002.tb03113.x - DOI - PubMed

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The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease

Affiliations

The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease

Authors

Affiliations

Abstract

Conflict of interest statement

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References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

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Medical