Am J Hum Genet. 2021 May 6;108(5):857-873. doi: 10.1016/j.ajhg.2021.04.001.

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Norine Voisin ¹, Rhonda E Schnur ², Sofia Douzgou ³, Susan M Hiatt ⁴, Cecilie F Rustad ⁵, Natasha J Brown ⁶, Dawn L Earl ⁷, Boris Keren ⁸, Olga Levchenko ⁹, Sinje Geuer ¹⁰, Sarah Verheyen ¹¹, Diana Johnson ¹², Yuri A Zarate ¹³, Miroslava Hančárová ¹⁴, David J Amor ¹⁵, E Martina Bebin ¹⁶, Jasmin Blatterer ¹¹, Alfredo Brusco ¹⁷, Gerarda Cappuccio ¹⁸, Joel Charrow ¹⁹, Nicolas Chatron ²⁰, Gregory M Cooper ⁴, Thomas Courtin ⁸, Elena Dadali ⁹, Julien Delafontaine ²¹, Ennio Del Giudice ²², Martine Doco ²³, Ganka Douglas ²⁴, Astrid Eisenkölbl ²⁵, Tara Funari ²⁴, Giuliana Giannuzzi ¹, Ursula Gruber-Sedlmayr ²⁶, Nicolas Guex ²⁷, Delphine Heron ⁸, Øystein L Holla ²⁸, Anna C E Hurst ²⁹, Jane Juusola ²⁴, David Kronn ³⁰, Alexander Lavrov ⁹, Crystle Lee ³¹, Séverine Lorrain ³², Else Merckoll ³³, Anna Mikhaleva ¹, Jennifer Norman ³⁴, Sylvain Pradervand ³⁵, Darina Prchalová ¹⁴, Lindsay Rhodes ²⁴, Victoria R Sanders ¹⁹, Zdeněk Sedláček ¹⁴, Heidelis A Seebacher ¹¹, Elizabeth A Sellars ¹³, Fabio Sirchia ³⁶, Toshiki Takenouchi ³⁷, Akemi J Tanaka ³⁸, Heidi Taska-Tench ¹⁹, Elin Tønne ⁵, Kristian Tveten ²⁸, Giuseppina Vitiello ²², Markéta Vlčková ¹⁴, Tomoko Uehara ³⁷, Caroline Nava ⁸, Binnaz Yalcin ³⁹, Kenjiro Kosaki ³⁷, Dian Donnai ³, Stefan Mundlos ¹⁰, Nicola Brunetti-Pierri ¹⁸, Wendy K Chung ³⁸, Alexandre Reymond ⁴⁰Affiliations expand

Abstract

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Keywords: AFF3; AFF4; horseshoe kidney; intellectual disability; mesomelic dysplasia.

• PMID: 33961779
• DOI: 10.1016/j.ajhg.2021.04.001

The UNIL web magasine L’Actu published an interview of Prof. A. Reymond and Dr N.Voisin regarding this article: https://news.unil.ch/display/1618579615668