Evidence map›Paper›PMID 38811945›Full record

ArticleGenome medicine2024

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra and 44 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

54 authors.

Sissy BassaniCenter for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, CH, 1015, Switzerland.
Jacqueline ChrastCenter for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, CH, 1015, Switzerland.
Giovanna AmbrosiniBioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
Norine VoisinCenter for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, CH, 1015, Switzerland.
Frédéric SchützBiostatistics Platform, University of Lausanne, Lausanne, Switzerland.
Alfredo BruscoDepartment of Neurosciences Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy.
Fabio SirchiaDepartment of Neurosciences Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy.
Lydia TurbanInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Susanna SchubertInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Jan-Ulrich SchlumpDepartment of Pediatrics, Centre for Neuromedicine, Gemeinschaftskrankenhaus Herdecke Gerhard-Kienle-Weg, Herdecke, Germany.
Desiree DeMilleGenomics Analysis 396, ARUP Laboratories, Salt Lake City, UT, USA.
Pinar Bayrak-ToydemirPediatric Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Gary Rex NelsonPediatric Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Kristen Nicole WongPediatric Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Laura DuncanDepartment of Pediatrics, Medical Center North, Vanderbilt University Medical Center, Nashville, TN, USA.
Mackenzie MoseraDepartment of Pediatrics, Medical Center North, Vanderbilt University Medical Center, Nashville, TN, USA.
Christian GilissenDepartment of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Lisenka E L M VissersDepartment of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph PfundtDepartment of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Rogier KersseboomCenter for Genetic Developmental Disorders Southwest, Zuidwester, Middelharnis, The Netherlands.
Hilde YttervikDepartment of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
Geir Åsmund Myge HansenDepartment of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
Marie Falkenberg SmelandDepartment of Pediatric Rehabilitation, University Hospital of North Norway, Tromsø, Norway.
Kameryn M ButlerGreenwood Genetic Center, Greenwood, SC, USA.
Michael J LyonsGreenwood Genetic Center, Greenwood, SC, USA.
Claudia M B CarvalhoPacific Northwest Research Institute (PNRI), Broadway, Seattle, WA, USA.
Chaofan ZhangDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
James R LupskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Lorraine PotockiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Leticia Flores-GallegosHospital Ángeles Puebla, Puebla, Mexico.
Rodrigo Morales-ToqueroHospital Ángeles Puebla, Puebla, Mexico.
Florence PetitCHU Lille, Clinique de Génétique, 59000, Lille, France.
Binnaz YalcinInserm UMR1231, University of Burgundy, 21000, Dijon, France.
Annabelle TuttleGeneDx, Gaithersburg, MD, USA.
Houda Zghal ElloumiGeneDx, Gaithersburg, MD, USA.
Lane McCormickDepartment of Genetics, Cook Children's Medical Center, Cook Children's Health Care System, Fort Worth, TX, USA.
Mary KukolichDepartment of Genetics, Cook Children's Medical Center, Cook Children's Health Care System, Fort Worth, TX, USA.
Oliver KlaasInstitute for Human Genetics, University Hospital Muenster, Muenster, Germany.
Judit HorvathInstitute for Human Genetics, University Hospital Muenster, Muenster, Germany.
Marcello ScalaDepartment of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, 16132, Italy.
Michele IacominoMedical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Francesca OpertoDepartment of Medicine, Child and Adolescent Neuropsychiatry Unit, Surgery and Dentistry, University of Salerno, Salerno, Italy.
Federico ZaraDepartment of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, 16132, Italy.
Karin WritzlClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Aleš MaverClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Maria K HaanpääDepartment of Genomics, Turku University Hospital, Turku, Finland; University of Turku, Turku, Finland.
Pia PohjolaDepartment of Genomics, Turku University Hospital, Turku, Finland; University of Turku, Turku, Finland.
Harri ArikkaDepartment of Pediatric Neurology, Turku University Hospital, Turku, Finland; University of Turku, Turku, Finland.
Anneke J A KievitDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Camilla CalandriniDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Christian IseliBioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
Nicolas GuexBioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
Alexandre ReymondCenter for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, CH, 1015, Switzerland. alexandre.reymond@unil.ch.ORCID 0000-0003-1030-8327

Funding

Frequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohortU01HG011758 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI RICHARD A GIBBS, JAMES R. LUPSKI · 2021 to 2026
$13.8M
STRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0M
NHGRI NIH HHS U01 HG011758NINDS NIH HHS R35 NS105078Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung 31003A_182632Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung IZSTZ0_216615Wellcome Trust WT223718/Z/21/Z
6 · The paper itself

Abstract

backgroundWe previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

methodsEvolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

resultsWe identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. 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 AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 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 AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.

conclusionsOur results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Indexed as

Intellectual DisabilityTranscriptomeZebrafishAnimalsFemaleHumansLoss of Function MutationMaleMutation, MissenseNuclear ProteinsPhenotypeAFF3 protein, humanNuclear ProteinsHorseshoe kidneyIntellectual disabilityMesomelic dysplasiaTranscriptomeZebrafish model

Identifiers

PMID38811945
PMCPMC11137988

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.