6533b872fe1ef96bd12d422e
RESEARCH PRODUCT
SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
Gilles MorinKrista BluskeNathaniel H. RobinLaurence FaivreManuela PrioloDihong ZhouEvangeline Kurtz-nelsonTianyun WangOmar SherbiniDaryl A. ScottKaren StalsFabíola Paoli MonteiroKaifang PangSara CabetFrancesca Clementina RadioBruno DallapiccolaMarjon Van SlegtenhorstRachel K. EarlKatheryn GrandMaria IasconeAlice S. BrooksAngelo SelicorniJuly K. Jean CuevasPaolo GaspariniPaolo GaspariniMaria Lisa DenticiMarialetizia MottaBritt-marie AnderlidKristin LindstromBerrin MonteleoneAndrea CiolfiKarin WeissKatharina SteindlKirsty McwalterRosalba CarrozzoRuben BoersHelen KingstonKym M. BoycottBekim SadikovicLaura Schultz-rogersEvan E. EichlerLaura A CrossAlison M R CastleLouisa KalsnerLucia PedaceMarijke R. WeversJohn M. GrahamJessica SebastianAntonio VitobelloGaetan LescaAlexander P.a. StegmannSuneeta Madan-khetarpalTahsin Stefan BarakatAbdallah F. EliasTeresa Robert FinestraAdeline VanderverAdeline VanderverPeter D. TurnpennyBregje W.m. Van BonAida TelegrafiDavid J. AmorDeepali N. ShindePedro A. Sanchez-laraLisenka E.l.m. VissersAdam JacksonAdam JacksonRolph PfundtAlessandro BrusellesAndres Hernandez-garciaKarin E. M. DiderichFlavio FaletraDana H. GoodloeJoanne BaezSarit RavidRomano TenconiSarah L. SawyerLynn PaisBronwyn KerrJoost GribnauLauren CarterMelissa T. CarterZhandong LiuJennifer L. KemppainenJennifer MackenzieJimmy HolderElke De BoerMargaret AuTaila HartleyCarol J SaundersLuciana MusanteBert B.a. De VriesTania Vertemati SecchesHaley McconkeyWillow SheehanFrancesca PantaleoniCaterina ZanusChristophe PhilippeChelsea RoadhouseStefania Lo CiceroSian EllardR. Tanner HagelstromMegha DesaiFernando KokJoset PascalMarco TartagliaEric W. KleeEva MoravaMichael A. LevyPeggy KulchLyndon GallacherErica L. MackeEmilia StellacciSiddharth BankaSiddharth BankaKristin G. MonaghanAnita RauchMeghan C. TowneKate Chandlersubject
0301 basic medicineSHARPMaleobesitygenotype-phenotype correlationsAutism Spectrum DisorderPROTEINChromosome DisordersHaploinsufficiencyRNA-Binding ProteinPHENOTYPE CORRELATIONS1p36; distal 1p36 deletion syndrome; DNA methylome analysis; episignature; genotype-phenotype correlations; neurodevelopmental disorder; obesity; proximal 1p36 deletion syndrome; SPEN; X chromosome; Adolescent; Autism Spectrum Disorder; Child; Child Preschool; Chromosome Deletion; Chromosome Disorders; Chromosomes Human Pair 1; Chromosomes Human X; DNA Methylation; DNA-Binding Proteins; Epigenesis Genetic; Female; Haploinsufficiency; Humans; Intellectual Disability; Male; Neurodevelopmental Disorders; Phenotype; RNA-Binding Proteins; Young AdultEpigenesis GeneticX chromosome0302 clinical medicineNeurodevelopmental disorderNeurodevelopmental DisorderIntellectual disabilityMOLECULAR CHARACTERIZATIONdistal 1p36 deletion syndromeChildGenetics (clinical)X chromosomeGeneticsXDNA methylome analysiRNA-Binding ProteinsSPLIT-ENDSHypotoniaDNA-Binding ProteinsPhenotypeAutism spectrum disorderChromosomes Human Pair 1Child PreschoolDNA methylome analysisMONOSOMY 1P36Pair 1SPENFemalemedicine.symptomChromosome DeletionHaploinsufficiencyRare cancers Radboud Institute for Health Sciences [Radboudumc 9]HumanAdolescentDNA-Binding ProteinBiologygenotype-phenotype correlationChromosomes03 medical and health sciencesYoung AdultGeneticSDG 3 - Good Health and Well-beingReportIntellectual DisabilityREVEALSGeneticsmedicineHumansEpigeneticsPreschoolChromosomes Human XNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]1p361p36 deletion syndromeIDENTIFICATIONMUTATIONSproximal 1p36 deletion syndromeDNA Methylationmedicine.diseaseneurodevelopmental disorderGENEepisignature030104 developmental biologyChromosome DisorderNeurodevelopmental Disorders030217 neurology & neurosurgeryEpigenesisdescription
Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-03-04 |