BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.

Peron, AngelaAngelaPeronD'Arco, FeliceFeliceD'ArcoAldinger, Kimberly AKimberly AAldingerSmith-Hicks, ConstanceConstanceSmith-HicksZweier, ChristianeChristianeZweierGradek, Gyri AGyri AGradekBradbury, KimberleyKimberleyBradburyAccogli, AndreaAndreaAccogliAndersen, Erica FErica FAndersenAu, Ping Yee BilliePing Yee BillieAuBattini, RobertaRobertaBattiniBeleford, DaniahDaniahBelefordBird, Lynne MLynne MBirdBouman, ArjanArjanBoumanBruel, Ange-LineAnge-LineBruelBusk, Øyvind LøvoldØyvind LøvoldBuskCampeau, Philippe MPhilippe MCampeauCapra, ValeriaValeriaCapraCarlston, ColleenColleenCarlstonCarmichael, JennyJennyCarmichaelChassevent, AnnaAnnaChasseventClayton-Smith, JillJillClayton-SmithBamshad, Michael JMichael JBamshadEarl, Dawn LDawn LEarlFaivre, LaurenceLaurenceFaivrePhilippe, ChristopheChristophePhilippeFerreira, PatrickPatrickFerreiraGraul-Neumann, LuitgardLuitgardGraul-NeumannGreen, Mary JMary JGreenHaffner, DarrahDarrahHaffnerHaldipur, ParthivParthivHaldipurHanna, SuhairSuhairHannaHouge, GunnarGunnarHougeJones, Wendy DWendy DJonesKraus, CorneliaCorneliaKrausKristiansen, Birgit ElisabethBirgit ElisabethKristiansenLespinasse, JamesJamesLespinasseLow, Karen JKaren JLowLynch, Sally AnnSally AnnLynchMaia, SofiaSofiaMaiaMao, RongRongMaoKalinauskiene, RutaRutaKalinauskieneMelver, CatherineCatherineMelverMcDonald, KimberlyKimberlyMcDonaldMontgomery, TaraTaraMontgomeryMorleo, ManuelaManuelaMorleoMotter, ConstanceConstanceMotterOpenshaw, Amanda SAmanda SOpenshawPalumbos, Janice CoxJanice CoxPalumbosParikh, Aditi ShahAditi ShahParikhPerilla-Young, YezminYezminPerilla-YoungPowell, Cynthia MCynthia MPowellPerson, RichardRichardPersonDesai, MeghaMeghaDesaiPiard, JulietteJuliettePiardPfundt, RolphRolphPfundtScala, MarcelloMarcelloScalaSerey-Gaut, MargauxMargauxSerey-GautShears, DeborahDeborahShearsSlavotinek, AnneAnneSlavotinekSuri, MohnishMohnishSuriTurner, ClaireClaireTurnerTvrdik, TatianaTatianaTvrdikWeiss, KarinKarinWeissWentzensen, Ingrid MIngrid MWentzensenZollino, MarcellaMarcellaZollinoHsieh, Tzung-ChienTzung-ChienHsiehde Vries, Bert B ABert B Ade VriesGuillemot, FrancoisFrancoisGuillemotDobyns, William BWilliam BDobynsViskochil, DavidDavidViskochilDias, CristinaCristinaDias2024-11-212024-11-212025-03https://boris-portal.unibe.ch/handle/20.500.12422/189470An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.en600 - Technology::610 - Medicine & healthBCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.article10.48620/764413944879910.1038/s41431-024-01701-z