6533b825fe1ef96bd128275b
RESEARCH PRODUCT
BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
ØYvind L. BuskKimberley BradburyArjan BoumanPhilippe M. CampeauLynne M. BirdLynne M. BirdCornelia KrausColleen CarlstonRong MaoJuliette PiardLaurence FaivreAmanda OpenshawCatherine Ward MelverMohnish SuriChristiane ZweierChristiane ZweierFrançois GuillemotRolph PfundtJanice C. PalumbosParthiv HaldipurJane A. HurstKimberly McdonaldMargaux Serey-gautMargaux Serey-gautLuitgard Graul-neumannKaren J. LowJenny CarmichaelPatrick FerreriraBirgit Elisabeth KristiansenAnge-line BruelConstance MotterAndrea AccogliAndrea AccogliDarrah N. HaffnerSuhair HannaSuhair HannaRuta MarcinkuteRuta MarcinkuteAngela PeronAngela PeronMarcella ZollinoSofia MaiaJames LespinasseClaire E. TurnerSally Ann LynchRichard E. PersonValeria CapraKimberly A. AldingerKimberly A. AldingerConstance Smith-hicksConstance Smith-hicksGyri Aasland GradekIngrid M. WentzensenMegha DesaiManuela MorleoAditi Shah ParikhAditi Shah ParikhMarcello ScalaMarcello ScalaCristina DiasCristina DiasCristina DiasGunnar HougeTelethon Undiagnosed Disease ProgramAnne SlavotinekRoberta BattiniMary J. GreenAnna ChasseventTara MontgomeryDavid ViskochilTatiana TvrdikDawn L. EarlDawn L. EarlKarin WeissKarin WeissFelice D'arcoWilliam B. DobynsWilliam B. DobynsPing Yee Billie AuDaniah BelefordErica F. AndersenErica F. AndersenBert B.a. De VriesJill Clayton-smithJill Clayton-smithChristophe PhilippeMichael J. BamshadMichael J. Bamshadsubject
business.industryPostnatal microcephalyMicrodeletion syndromemedicine.diseaseBioinformaticsHypotoniaDevelopmental disorderAutism spectrum disorderIntellectual disabilityFetal hemoglobinmedicineMissense mutationmedicine.symptombusinessdescription
AbstractPurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.ConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-09-15 |