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RESEARCH PRODUCT
De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
Laurence PerrinMarjolijn C.j. JongmansMarjolijn C.j. JongmansIsabelle ThiffaultIsabelle ThiffaultHan G. BrunnerHan G. BrunnerBethany PeriSarah K. BartzAlexandra AfenjarKristina BaltrunaiteEsmé WaandersJayne Y. Hehir-kwaIllja J. DietsBoris KerenAlexander J. M. DingemansGea BeundersRoland P. KuiperAnneke T. Vulto-van SilfhoutLaurens WielBert CallewaertAndrew DauberMargot R.f. ReijndersMargot R.f. ReijndersTjitske KleefstraVivian HwaCaroline NavaMatias WagnerMatthias GrieseLina Huerta-saenzLina Huerta-saenzRoos Van Der DonkRolph PfundtNicoline HoogerbruggeChristian GilissenMaxime Cadieux-dionJulia VodopiutzKoen L.i. Van GassenAnnekatrien BoelJulien ThevenonNienke E. VerbeekBert B.a. De VriesVassiliki Konstantopoulousubject
0301 basic medicineMaleJumonji Domain-Containing Histone DemethylasesDevelopmental DisabilitiesWEAVER SYNDROMEPROTEINHaploinsufficiencyCraniofacial AbnormalitiesHistones0302 clinical medicineIntellectual disabilityTumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14]Missense mutationDEMETHYLASE KDM3BExomeChildGenetics (clinical)Exome sequencingGeneticsRUBINSTEIN-TAYBI SYNDROMEMetabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]Phenotype030220 oncology & carcinogenesisFemalemedicine.symptomHaploinsufficiencyRare cancers Radboud Institute for Health Sciences [Radboudumc 9]Joint hypermobilityGENETICSJMJD1CMutation MissenseDwarfismBiologyShort statureKdm3b ; Cancer Predisposition ; Developmental Delay ; Facial Recognition ; Intellectual Disability ; Leukemia ; Lymphoma ; Short Stature03 medical and health sciencesReportIntellectual DisabilitymedicineHumansMYELOID-LEUKEMIAGenetic Association StudiesGerm-Line MutationWeaver syndromeNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Rubinstein–Taybi syndromeMUTATIONSDELETIONGenetic Variationmedicine.diseaseBody HeightMusculoskeletal AbnormalitiesINDIVIDUALS030104 developmental biologyFaceNanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]description
Contains fulltext : 202646.pdf (Publisher’s version ) (Open Access) By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-04-04 | American Journal of Human Genetics |