Variants in the degron of<i>AFF3</i>cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

<jats:title>Abstract</jats:title><jats:p>The ALF transcription factor paralogs,<jats:italic>AFF1, AFF2, AFF3</jats:italic>and<jats:italic>AFF4</jats:italic>, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated with<jats:italic>de novo</jats:italic>missense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role of<jats:italic>AFF3</jats:italic>variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe<jats:underline>KI</jats:underline>dney, NS for<jats:underline>N</jats:underline>ievergelt/<jats:underline>S</jats:underline>avarirayan type of mesomelic dysplasia, S for<jats:underline>S</jats:underline>eizures, H for<jats:underline>H</jats:underline>ypertrichosis, I for<jats:underline>I</jats:underline>ntellectual disability and P for<jats:underline>P</jats:underline>ulmonary involvement), partially overlapping the<jats:italic>AFF4</jats:italic>associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif of<jats:italic>AFF3</jats:italic>exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.</jats:p><jats:p>Whereas homozygous<jats:italic>Aff3</jats:italic>knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.</jats:p><jats:p>Transcriptome analyses as well as the partial phenotypic overlap of syndromes associated with<jats:italic>AFF3</jats:italic>and<jats:italic>AFF4</jats:italic>variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested</jats:p>