Navigating Uncertainty: Explorative Study of Factors Influencing Carrier Testing in Siblings of Individuals with Purine and Pyrimidine Metabolism Disorders
Ethical Legal Social Issues (ELSI) Public Health and Policy
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Primary Categories:
- Genetic Counseling
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Secondary Categories:
- Genetic Counseling
Introduction:
Genetic counseling for rare diseases can be challenging, given the limited literature available and the variable presentation of many rare diseases, including disorders of purine and pyrimidine metabolism (DPPM). Current recommendations from the American College of Medical Genetics (ACMG) do not support targeted carrier testing of unaffected minors for recessive conditions. In rare diseases, with medically ambiguous language, limited understanding of natural history, and limited treatment available, parents and family members frequently experience uncertainty. Many rare disease families pursue carrier testing for asymptomatic siblings of affected individuals even when it is not supported by the current ACMG recommendations. In this study, we seek to characterize the uptake of carrier testing in DPPM families and understand factors driving decisions to test or not test.
Methods:
Participants were enrolled at the NIH Clinical Center through an IRB approved protocol (HG-001625). We reviewed records with biological parents and siblings of affected individuals and collected data regarding their decisions to pursue carrier testing, age of testing, need for bioethics review, and testing outcomes.
For future in-depth interviews: sample selection will include family members of affected individuals enrolled in a DPPM natural history protocol (ClinicalTrials.gov ID, NCT06092346), including parents and siblings. Interviews can be conducted in person or virtually. Transcription software may be utilized, and we will analyze the transcripts to determine the main themes, including factors influencing decision-making for carrier testing. A codebook will be created for qualitative data analysis.
Results:
There are currently fourteen individuals (11 families) with DPPM enrolled in the protocol, with Lesch-Nyhan disease (n=6), adenylosuccinate lyase deficiency (n=3), and phosphoribosylpyrophosphate synthetase deficiency (n=3), and adenylosuccinate synthase 1 (n=2). Eighty percent of the families self-identified as white and non-Hispanic. The age range of the affected individuals is 2 years to 25 years of age.
Of the 9 siblings of affected individuals, 3 have completed carrier testing (33%), all before age 18 years. A bioethics review was requested for 2 of 3 minors prior to carrier testing. One enrolled affected participant is a minor and was asymptomatic when carrier screening (genetic testing) was elected. Genetic testing was pursued per parental request, due to the recent diagnosis of their older child.
Conclusion:
Preliminary results suggest that some DPPM families may cope with uncertainty through information-seeking actions like pursuing genetic testing for asymptomatic siblings of affected family members. Future in-depth interviews will provide the opportunity to assess the role of carrier/genetic testing in families of rare diseases. It may reveal the effect of genetic testing on interactions with healthcare and other social systems, intrafamilial communication regarding the diagnosis, and coping strategies adopted by family members and caregivers. This research will improve understanding of the uptake and downstream effects of predictive genetic testing in families affected by DPPM, and rare diseases more broadly.
Genetic counseling for rare diseases can be challenging, given the limited literature available and the variable presentation of many rare diseases, including disorders of purine and pyrimidine metabolism (DPPM). Current recommendations from the American College of Medical Genetics (ACMG) do not support targeted carrier testing of unaffected minors for recessive conditions. In rare diseases, with medically ambiguous language, limited understanding of natural history, and limited treatment available, parents and family members frequently experience uncertainty. Many rare disease families pursue carrier testing for asymptomatic siblings of affected individuals even when it is not supported by the current ACMG recommendations. In this study, we seek to characterize the uptake of carrier testing in DPPM families and understand factors driving decisions to test or not test.
Methods:
Participants were enrolled at the NIH Clinical Center through an IRB approved protocol (HG-001625). We reviewed records with biological parents and siblings of affected individuals and collected data regarding their decisions to pursue carrier testing, age of testing, need for bioethics review, and testing outcomes.
For future in-depth interviews: sample selection will include family members of affected individuals enrolled in a DPPM natural history protocol (ClinicalTrials.gov ID, NCT06092346), including parents and siblings. Interviews can be conducted in person or virtually. Transcription software may be utilized, and we will analyze the transcripts to determine the main themes, including factors influencing decision-making for carrier testing. A codebook will be created for qualitative data analysis.
Results:
There are currently fourteen individuals (11 families) with DPPM enrolled in the protocol, with Lesch-Nyhan disease (n=6), adenylosuccinate lyase deficiency (n=3), and phosphoribosylpyrophosphate synthetase deficiency (n=3), and adenylosuccinate synthase 1 (n=2). Eighty percent of the families self-identified as white and non-Hispanic. The age range of the affected individuals is 2 years to 25 years of age.
Of the 9 siblings of affected individuals, 3 have completed carrier testing (33%), all before age 18 years. A bioethics review was requested for 2 of 3 minors prior to carrier testing. One enrolled affected participant is a minor and was asymptomatic when carrier screening (genetic testing) was elected. Genetic testing was pursued per parental request, due to the recent diagnosis of their older child.
Conclusion:
Preliminary results suggest that some DPPM families may cope with uncertainty through information-seeking actions like pursuing genetic testing for asymptomatic siblings of affected family members. Future in-depth interviews will provide the opportunity to assess the role of carrier/genetic testing in families of rare diseases. It may reveal the effect of genetic testing on interactions with healthcare and other social systems, intrafamilial communication regarding the diagnosis, and coping strategies adopted by family members and caregivers. This research will improve understanding of the uptake and downstream effects of predictive genetic testing in families affected by DPPM, and rare diseases more broadly.