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

1 UNIL - Université de Lausanne = University of Lausanne
2 CMSRU - Cooper Medical School of Rowan University [Camden]
3 MFT - Manchester University NHS Foundation Trust
4 University of Manchester [Manchester]
5 HudsonAlpha Institute for Biotechnology [Huntsville, AL]
6 Oslo University Hospital [Oslo]
7 VCGS - Victorian Clinical Genetics Services [Melbourne, VIC, Australia]
8 MCRI - Murdoch Children's Research Institute
9 University of Melbourne
10 Seattle Children’s Hospital
11 CHU Pitié-Salpêtrière [AP-HP]
12 RCMG - Research Centre for Medical Genetics [Moscow, Russia]
13 MPIMG - Max Planck Institute for Molecular Genetics
14 Medical University of Graz
15 Sheffield Children's NHS Foundation Trust
16 University of Arkansas at Little Rock
17 UK - Univerzita Karlova [Praha, Česká republika] = Charles University [Prague, Czech Republic]
18 University Hospital Motol [Prague]
19 UAB - University of Alabama at Birmingham [ Birmingham]
20 UNITO - Università degli studi di Torino = University of Turin
21 Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino
22 University of Naples Federico II = Università degli studi di Napoli Federico II
23 Ann & Robert H. Lurie Children's Hospital of Chicago
24 SIB - Swiss Institute of Bioinformatics [Lausanne]
25 HERVI - EA 3801 - Hémostase et Remodelage Vasculaire Post-Ischémie
26 GeneDx [Gaithersburg, MD, USA]
27 JKU - University of Linz - Johannes Kepler Universität Linz
28 Telemark Hospital Trust [Skien, Norway]
29 NYMC - New York Medical College
30 IPN - Integris Pediatric Neurology [Oklahoma City, OK, USA]
31 Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” [Trieste]
32 Keio University School of Medicine [Tokyo, Japan]
33 Columbia University [New York]
34 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
35 MCGM - Manchester Centre for Genomic Medicine [Manchester, UK]
36 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]

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.

Mots clés: AFF3; AFF4; horseshoe kidney; intellectual disability; mesomelic dysplasia.

Domaines: Sciences du Vivant [q-bio]

Norine Voisin, Rhonda E Schnur, Sofia Douzgou, Susan M Hiatt, Cecilie F Rustad, et al.. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. American Journal of Human Genetics, 2021, 108, pp.857 - 873. ⟨10.1016/j.ajhg.2021.04.001⟩. ⟨inserm-03948529⟩