for the familial variant could be offered to symptomatic or presymptomatic relatives, who are at risk of developing renal failure or passing the genetic abnormality to their offspring. Couples with a known sequence variant may elect to have prenatal diagnosis or PGD if they wish to avoid having an affected child. If a relative of the proband tests negative, then none of their offspring are at risk and they will not need to be tested. There are key differences in the post-test consequences across the two populations proposed for genetic testing. For diagnostic genetic testing of an affected individual (proband), the consequences of a mutation being identified are relatively simple and can be readily incorporated into the care plans of their pre-existing specialist. On the other hand, unaffected family members who are shown by genetic testing to carry the mutation have more care pathways potentially available because they have yet to manifest the disease. The care pathways for these individuals will likely involve new consultations with a nephrologist and a clinical geneticist or genetic counsellor. For relatives that undergo cascade testing, liver biopsy is avoided. Proposed economic evaluation The clinical claim is that genetic testing for AS is superior in terms of clinical effectiveness and safety to no genetic testing (usual care, defined as diagnosis on the basis of history, clinical examination and family history, with or without renal biopsy). Genetic testing is more accurate in identifying individuals with AS who are at risk of early onset renal failure, SNHL, and ocular defects. Genetic testing provides prognostic information that could be used to guide treatment initiation and intensity. Earlier initiation of treatment (before the development of overt proteinuria) may delay the onset of renal failure, thereby improving HRQoL. Genetic testing enables appropriate reproductive counselling for those at risk of passing the genetic abnormality to their offspring. The appropriate economic evaluation is a cost-utility analysis, capturing the benefits of more accurate diagnosis and improved HRQoL due to early intervention and delayed onset and progression of renal failure in the proband and biological family members.
for the familial variant could be offered to symptomatic or presymptomatic relatives, who are at risk of developing renal failure or passing the genetic abnormality to their offspring. Couples with a known sequence variant may elect to have prenatal diagnosis or PGD if they wish to avoid having an affected child. If a relative of the proband tests negative, then none of their offspring are at risk and they will not need to be tested. There are key differences in the post-test consequences across the two populations proposed for genetic testing. For diagnostic genetic testing of an affected individual (proband), the consequences of a mutation being identified are relatively simple and can be readily incorporated into the care plans of their pre-existing specialist. On the other hand, unaffected family members who are shown by genetic testing to carry the mutation have more care pathways potentially available because they have yet to manifest the disease. The care pathways for these individuals will likely involve new consultations with a nephrologist and a clinical geneticist or genetic counsellor. For relatives that undergo cascade testing, liver biopsy is avoided. Proposed economic evaluation The clinical claim is that genetic testing for AS is superior in terms of clinical effectiveness and safety to no genetic testing (usual care, defined as diagnosis on the basis of history, clinical examination and family history, with or without renal biopsy). Genetic testing is more accurate in identifying individuals with AS who are at risk of early onset renal failure, SNHL, and ocular defects. Genetic testing provides prognostic information that could be used to guide treatment initiation and intensity. Earlier initiation of treatment (before the development of overt proteinuria) may delay the onset of renal failure, thereby improving HRQoL. Genetic testing enables appropriate reproductive counselling for those at risk of passing the genetic abnormality to their offspring. The appropriate economic evaluation is a cost-utility analysis, capturing the benefits of more accurate diagnosis and improved HRQoL due to early intervention and delayed onset and progression of renal failure in the proband and biological family members.