Year: 2025
Type: article
Abstract: Importance Genomic sequencing enables rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but less well understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation. Observations We explore the probability of subsequent disease following genetic screening of several of variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), comparing with screening for phenylketonuria which is well established. The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD, when testing repeat expansions for which the test had sub-optimal performance (sensitivity=99% and specificit =90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1, when testing pathogenic SNVs (sensitivity=99.96% and specificity=99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%). Conclusions and Relevance We show that risk following a positive screening test result can be strikingly low for rare neurological diseases. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols of very high sensitivity and specificity, careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings.
Source: Biomedicines
Institutions: King's College London, South London and Maudsley NHS Foundation Trust, NIHR Maudsley Biomedical Research Centre, Great Ormond Street Hospital, UCL Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, Guy's and St Thomas' NHS Foundation Trust, London School of Hygiene & Tropical Medicine, King's College Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,137
Funders: South London and Maudsley NHS Foundation Trust, MND Scotland, EU Joint Programme – Neurodegenerative Disease Research, UK Research and Innovation, Spastic Paraplegia Foundation, National Institute for Health and Care Research, Department of Health and Social Care, Motor Neurone Disease Association, King's College London, Rosetrees Trust, Alzheimer’s Research UK, National Institutes of Health, Horizon 2020 Framework Programme, NIHR Maudsley Biomedical Research Centre, Medical Research Council, Economic and Social Research Council, Queensland Brain Institute, National Human Genome Research Institute
Awards: G1394153703, A Programme for ALS Care in Europe (ALS-CarE), G1666093388, G1933305430, G1951662401, G1953418237, G2208823066, G2520054049, G2708743612, G2813660310, G2841891430, G292095858, G311130357, G3133244695, G3569089323, G3647243144, G3855231562, JPND Biological Resource Analysis to Identify New MEchanisms and phenotypes in Neurodegenerative Diseases (BRAIN-MEND), G409544044, G4566050907, G4657563902, G4732434853, G4736908603, G4868251782, G5020367745, G5216903785, G522893879, G5312864853, G5378239828, G546254809, G558236491, G5646656704, STRENGTH, G5924068501, G6073458244, G608667592, G6568403163, G6571361493, G7004701123, G7419370404, G7497421394, G7926424806, G8100370559, G8321349868, G8458666040, G8573914442, G8580352112, G8832015751, G8858395165, G9000219399
OpenAlex ID: W4409700798