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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 857-873 |
| Number of pages | 17 |
| Journal | American journal of human genetics |
| Volume | 108 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 6 2021 |
Funding
We thank the probands and their families for their participation in this study. We are grateful to Jacques S. Beckmann, Giedre Grigelioniene, and the Genomic Technologies Facility and the Protein Analysis Facility of the University of Lausanne. This work was supported by grants from the Swiss National Science Foundation (31003A_182632 to A.R.), The Simons Foundation (SFARI274424 to A.R. and SFARI337701 to W.K.C.), the JPB Foundation to W.K.C. the NHGRI (UM1HG007301 to S.M.H. E.M.B. G.M.C.), the Lejeune Foundation to A.R. and the Czech Ministry of Health (17-29423A to Z.S.). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (WT098051). The views expressed in this publication are those of the authors and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network. This study makes use of DECIPHER, which is funded by the Wellcome. We acknowledge the Sanger Mouse Genetics Project for providing mouse samples, funded by the Wellcome Trust (098051). The Australian National Health and Medical Research Council (NHMRC) provided funding for sequencing proband 13 under the Australian Genomics Health Alliance (GNT1113531); the contents are solely the responsibility of the individual authors and do not reflect the views of the NHMRC. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the probands and their families for their participation in this study. We are grateful to Jacques S. Beckmann, Giedre Grigelioniene, and the Genomic Technologies Facility and the Protein Analysis Facility of the University of Lausanne. This work was supported by grants from the Swiss National Science Foundation ( 31003A_182632 to A.R.), The Simons Foundation ( SFARI274424 to A.R. and SFARI337701 to W.K.C.), the JPB Foundation to W.K.C., the NHGRI ( UM1HG007301 to S.M.H., E.M.B., G.M.C.), the Lejeune Foundation to A.R., and the Czech Ministry of Health (17-29423A to Z.S.). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund ( HICF-1009-003 ), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute ( WT098051 ). The views expressed in this publication are those of the authors and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network. This study makes use of DECIPHER, which is funded by the Wellcome. We acknowledge the Sanger Mouse Genetics Project for providing mouse samples, funded by the Wellcome Trust ( 098051 ). The Australian National Health and Medical Research Council (NHMRC) provided funding for sequencing proband 13 under the Australian Genomics Health Alliance ( GNT1113531 ); the contents are solely the responsibility of the individual authors and do not reflect the views of the NHMRC. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords
- AFF3
- AFF4
- horseshoe kidney
- intellectual disability
- mesomelic dysplasia
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)