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In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in<jats:italic>LMNA<\/jats:italic>, and two additional variants, one each in<jats:italic>SETX<\/jats:italic>(g.intron10-13delCTT) and<jats:italic>FUS<\/jats:italic>(p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the<jats:italic>FUS<\/jats:italic>variant appears to be protective against the effects of the<jats:italic>SETX<\/jats:italic>and the<jats:italic>LMNA<\/jats:italic>variants on cell viability and may indicate loss of interaction of FUS with SETX and\/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.<\/jats:p>","DOI":"10.1007\/s11010-021-04103-7","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T05:02:57Z","timestamp":1614834177000},"page":"2633-2650","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype"],"prefix":"10.1007","volume":"476","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7601-4869","authenticated-orcid":false,"given":"Kathryn","family":"Volkening","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5936-0957","authenticated-orcid":false,"given":"Sali M. 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