{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:32:42Z","timestamp":1768566762155,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,17]]},"group-title":"Genetic and Genomic Medicine","reference-count":61,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by\n                    <jats:italic>de novo<\/jats:italic>\n                    variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in\n                    <jats:italic>AFF3<\/jats:italic>\n                    . We used both animal and cellular models to assess the deleteriousness of the identified variants.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We identified an individual with a KINSSHIP-like phenotype carrying a\n                    <jats:italic>de novo<\/jats:italic>\n                    partial duplication of\n                    <jats:italic>AFF3<\/jats:italic>\n                    further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in\n                    <jats:italic>AFF3<\/jats:italic>\n                    . Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human\n                    <jats:italic>AFF3<\/jats:italic>\n                    mRNA, confirming their association with the ablation of\n                    <jats:italic>aff3<\/jats:italic>\n                    . Conversely, some of the human\n                    <jats:italic>AFF3<\/jats:italic>\n                    mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated\n                    <jats:italic>AFF3<\/jats:italic>\n                    mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of\n                    <jats:italic>AFF3<\/jats:italic>\n                    variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +\/+, DN\/DN, LoF\/+, LoF\/LoF or DN\/LoF\n                    <jats:italic>AFF3<\/jats:italic>\n                    genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN\/DN or the LoF\/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that\n                    <jats:italic>AFF3<\/jats:italic>\n                    LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in\n                    <jats:italic>AFF3<\/jats:italic>\n                    function are deleterious.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.14.24301100","type":"posted-content","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T12:51:34Z","timestamp":1705495894000},"source":"Crossref","is-referenced-by-count":1,"title":["Variant-specific pathophysiological mechanisms of\n                  <i>AFF3<\/i>\n                  differently influence transcriptome 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