biostudies-literatureLessel IAustrian Science Fund FWFNICHD NIH HHSNHGRI NIH HHSNational Institute for Health Research (NIHR)NINDS NIH HHS394-413https://www.ebi.ac.uk/biostudies/studies/S-EPMC11866971biostudies-literatureUnknown112(2)BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes American journal of human geneticsDNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.PMC11866971U01 NS134350I 6657U01 HG007672NIHR203308R01 HD109342Tolosa EUndiagnosed Diseases NetworkHaack TBMancardi MElgizouli MIascone MNevay DLLeppala JWieczorek DLyon GJSebastian JChappe CLupski JRSchrauwen IAfenjar AAverdunk LNigro VChandler KEIsidor BHadonou MLessel DDeb WHarasink SMYuan BLessel IMadan-Khetarpal SPappas JBaresic AMaeding NCalle-Martin OKubisch CSzakszon KMay JPosey JEDubourg CKalinauskiene RKessler ELeal SMJosifova DDilena RJin JJRabin RBegtrup ARekab APlatzer KLuu SMBanka SMorel CFChong HJTan QKGMarchi EPastore MTMenendez BCapra VHuning IHanker BBrugger MCogne BKuechler AKamsteeg EJMehta LKeren BJorge AALChinn IKGucsavas-Calikoglu MBesnard TKolbel HSidlow RStrunk DRomano FWagner MFernandes EKozenko MRobert LBrager RGoenka ASullivan JByrne SCardenas PCope HOegema RScala MFitzgerald KKRezende RCBrick LBrunet TGangi SPoths KConboy EBedeschi MFPerilla-Young YCourtin TGeorge-Abraham JKShort JPowell-Hamilton NJarvela IOdent SfalseDNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes 2025-01-01T00:00:00Z2025 Feb2026-06-01T08:52:39.974Z2025-04-07T11:30:32.05ZS-EPMC118669713979856910.1016/j.ajhg.2024.12.012