A familial amyotrophic lateral sclerosis pedigree discordant for a novel p.Glu46Asp heterozygous OPTN variant and the p.Ala5Val heterozygous SOD1 missense mutation |
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| Affiliation: | 1. Neurophysiopathology Centre, Department of Diagnostics and Applied Technology, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy;2. Child Neurology Unit, Cesare Arrigo Children''s Hospital, Alessandria, Italy;3. ‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin, Turin, Italy;4. Neurology 1, ALS Center, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy;5. The NEMO Clinical Center (NEuroMuscular Onmicenter), Milan, Italy;6. Neurorehabilitation Unit, University of Milan, Milan, Italy;7. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa and IRCCS Policlinico San Martino, Genoa, Italy;8. IRCCS Policlinico San Martino, Genoa, Italy;9. Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy |
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| Abstract: | About 10% of Amyotrophic Lateral Sclerosis (ALS) cases are familial (FALS), mainly related to mutations in C9ORF72, SOD1, TARDBP, and FUS genes. Recent data revealed the presence of multiple variants in ALS-associated genes in FALS in excess of what is to be expected by chance. FALS patients not carrying a pathogenic genetic mutation detected in their kindred have been reported. We report a FALS case, who did not carry the p.Ala5Val heterozygous SOD1 mutation that had been detected in other affected subjects of his kindred. He underwent Next-Generation Sequencing, revealing a novel p.Glu46Asp heterozygous OPTN variant of uncertain significance (VUS). Discordant genetic test results in FALS cases within the same family and the detection of variants of uncertain significance increase the complexities of genetic counselling. |
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| Keywords: | Familial ALS Genetic variant of uncertain significance Genetic counselling |
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