Ethical considerations of population screening for late-onset genetic diseaseby K. Golden-Grant, J.L. Merritt, C.R. Scott

Clin Genet


Genetics (clinical) / Genetics


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Clin Genet 2015

Printed in Singapore. All rights reserved © 2015 John Wiley & Sons A/S.

Published by John Wiley & Sons Ltd

CLINICAL GENETICS doi: 10.1111/cge.12566

Short Report

Ethical considerations of population screening for late-onset genetic disease

Golden-Grant K., Merritt II J.L., Scott C.R. Ethical considerations of population screening for late-onset genetic disease.

Clin Genet 2015. © John Wiley & Sons A/S. Published by John Wiley &

Sons Ltd, 2015

Population-based genetic screening has been a mainstay of public health in the United States for many years. The goal of genetic screening is to identify individuals at increased risk for treatable diseases. The evolution of genetic testing to include multi-disease panels allows for new screening applications which challenge the traditional model of clinical genetics care by the identification of late-onset disorders in an asymptomatic fetus, child, or adult. We present two unique examples of individuals referred to a biochemical genetics clinic due to the detection of late-onset Pompe disease by population-based screening modalities. We review early experiences in counseling and management of pre-symptomatic individuals and highlight some of the primary ethical factors warranting consideration as we enter the era of genomic medicine.

Conflict of interest

The authors report no other acknowledgements or conflicts of interests.

K. Golden-Granta,

J.L. Merritt IIband C.R. Scottb aSeattle Children’s Hospital and bDepartment of Pediatrics, University of

Washington, Seattle, WA, USA

Key words: autonomy – beneficence – ethics – genetic screening – justice – newborn screening – non-maleficence – next-generation sequencing –

Pompe disease

Corresponding author: Kathryn

Golden-Grant, Department of

Pediatrics, Seattle Children’s Hospital,

M/S O.C.9.850, PO Box 5371, Seattle,

WA 98105, USA.

Tel.: +1206987 1389; fax: +1206 9872495; e-mail:

Received 19 December 2014, revised and accepted for publication 3

February 2015

Population-based screening is intended to identify individuals at increased risk for disease with the goal of providing an improved health outcome for affected individuals by early initiation of available therapies (1). The two most prevalent population-based screening programs – prenatal carrier screening and newborn screening (NBS) – have rapidly expanded in the past decade. Prenatal carrier screening transitioned from ethnicity-based to universal carrier screening utilizing untargeted screening panels (2, 3). Some universal panels provide carrier information for over 100 recessive disorders including some considered to be mild or to have adult-onset presentations (4). State programs have similarly experienced significant growth through the use of tandem mass spectrometry to detect fatty acid oxidation disorders, amino acidopathies, and organic acidemias and now continue their expansion to include the lysosomal storage disorders (5, 6). Prenatal and newborn screening platforms will continue to expand because of the rapid progression in genomic sequencing technologies and applications (7).

These advances in screening technologies now permit the identification of individuals with late-onset disease, creating so-called ‘patients in waiting’ – those with a genetic diagnosis but without clinical symptoms and without indication for treatment initiation (8).

The aim of this paper is to encourage discussion of the ethical considerations related to population screening for mild and late-onset disorders. We highlight this topic by sharing two unique patients diagnosed with late-onset

Pompe disease by prenatal carrier screening. Pompe disease provides an excellent example for this discussion because of its significant variability in age of onset and symptom severity, as well as our incomplete knowledge of genotype–phenotype correlations.

Pompe disease background

Pompe disease is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid alpha-glucosidase (GAA) which results from mutations in the gene GAA (9). Enzyme activity is generally lower in individuals with infantile-onset Pompe disease compared to those with adult-onset disease; however, there is overlap and the two forms are sometimes indistinguishable by enzyme measurement. As of 2012, there 1

Golden-Grant et al. were 248 known pathogenic mutations in the GAA (10).

Although genotype may help predict disease course, there are other unknown factors which influence age of onset and disease progression (11, 12).

The GAA IVS1-13T>G mutation has a residual enzyme activity of 20–40% and is present in around 71% of people with late-onset Pompe disease worldwide. This mutation has not been identified in patients with infantile-onset Pompe (13, 14). There is significant phenotypic variability among individuals with the IVS1-3T>G mutation which appears to be dependent upon the nature of the paired mutation (13, 15).

Homozygosity for IVS1-13T>G has been hypothesized to result in an asymptomatic presentation and has been described in a single report of a French female with onset of myopathy at age 35 years, 90% forced vital capacity, and 11% residual GAA activity (13, 16).

Management for late-onset Pompe disease involves a multi-disciplinary medical team and GAA enzyme replacement therapy (ERT) (17). In the infantile Pompe population, ERT has been well-documented to show significant effectiveness in reversing and preventing hypertrophic cardiomyopathy and extending life expectancy (9). ERT appears to be less efficacious in the late-onset

Pompe population, with only modest improvements in muscle strength and respiratory function and limited improvement in quality of life (9, 18). Current management guidelines indicate that ERT should be initiated when a patient first becomes symptomatic (17).

Methods and materials

We report the experience of two presymptomatic individuals presenting to the Biochemical Genetics program at the University of Washington and Seattle Children’s