Sheppard, Sarah ESarah ESheppardBryant, LauraLauraBryantWickramasekara, Rochelle NRochelle NWickramasekaraVaccaro, CourtneyCourtneyVaccaroRobertson, BrynnBrynnRobertsonHallgren, JodiJodiHallgrenHulen, JasonJasonHulenWatson, Cynthia JCynthia JWatsonFaundes, VictorVictorFaundesDuffourd, YannisYannisDuffourdLee, PearlPearlLeeSimon, M CelesteM CelesteSimonde la Cruz, XavierXavierde la CruzPadilla, NatáliaNatáliaPadillaFlores-Mendez, MarcoMarcoFlores-MendezAkizu, NaiaraNaiaraAkizuSmiler, JacquelineJacquelineSmilerPellegrino Da Silva, RenataRenataPellegrino Da SilvaLi, DongDongLiMarch, MichaelMichaelMarchDiaz-Rosado, AbdiasAbdiasDiaz-RosadoPeixoto de Barcelos, IsabellaIsabellaPeixoto de BarcelosChoa, Zhao XiangZhao XiangChoaLim, Chin YanChin YanLimDubourg, ChristèleChristèleDubourgJournel, HubertHubertJournelDemurger, FlorenceFlorenceDemurgerMulhern, MaureenMaureenMulhernAkman, CigdemCigdemAkmanLippa, NatalieNatalieLippaAndrews, MarisaMarisaAndrewsBaldridge, DustinDustinBaldridgeConstantino, JohnJohnConstantinovan Haeringen, ArieArievan HaeringenSnoeck-Streef, IrinaIrinaSnoeck-StreefChow, PennyPennyChowHing, AnneAnneHingGraham, John MJohn MGrahamAu, MargaretMargaretAuFaivre, LaurenceLaurenceFaivreShen, WeiWeiShenMao, RongRongMaoPalumbos, JaniceJanicePalumbosViskochil, DavidDavidViskochilGahl, WilliamWilliamGahlTifft, CynthiaCynthiaTifftMacnamara, EllenEllenMacnamaraHauser, NatalieNatalieHauserMiller, RebeccaRebeccaMillerMaffeo, JessicaJessicaMaffeoAfenjar, AlexandraAlexandraAfenjarDoummar, DianeDianeDoummarKeren, BorisBorisKerenArn, PamelaPamelaArnMacklin-Mantia, SarahSarahMacklin-MantiaMeerschaut, IlseIlseMeerschautCallewaert, BertBertCallewaertReis, AndréAndréReisZweier, Christiane GertrudChristiane GertrudZweierBrewer, CaroleCaroleBrewerSaggar, AnandAnandSaggarSmeland, Marie FMarie FSmelandKumar, AjithAjithKumarElmslie, FrancesFrancesElmslieDeshpande, CharuCharuDeshpandeNizon, MathildeMathildeNizonCogne, BenjaminBenjaminCognevan Ierland, YvetteYvettevan IerlandWilke, MartinaMartinaWilkevan Slegtenhorst, MarjonMarjonvan SlegtenhorstKoudijs, SuzanneSuzanneKoudijsChen, Jin YunJin YunChenDredge, DavidDavidDredgePier, DanielleDaniellePierWortmann, SaskiaSaskiaWortmannKamsteeg, Erik-JanErik-JanKamsteegKoch, JohannesJohannesKochHaynes, DevonDevonHaynesPollack, LyndaLyndaPollackTitheradge, HannahHannahTitheradgeRanguin, KaraKaraRanguinDenommé-Pichon, Anne-SophieAnne-SophieDenommé-PichonWeber, SachaSachaWeberPérez de la Fuente, RubénRubénPérez de la FuenteSánchez Del Pozo, JaimeJaimeSánchez Del PozoLezana Rosales, Jose MiguelJose MiguelLezana RosalesJoset, PascalPascalJosetSteindl, KatharinaKatharinaSteindlRauch, AnitaAnitaRauchMei, DavideDavideMeiMari, FrancescoFrancescoMariGuerrini, RenzoRenzoGuerriniLespinasse, JamesJamesLespinasseTran Mau-Them, FrédéricFrédéricTran Mau-ThemPhilippe, ChristopheChristophePhilippeDauriat, BenjaminBenjaminDauriatRaymond, LaureLaureRaymondMoutton, SébastienSébastienMouttonCueto-González, Anna MAnna MCueto-GonzálezTan, Tiong YangTiong YangTanMignot, CyrilCyrilMignotGrotto, SarahSarahGrottoRenaldo, FlorenceFlorenceRenaldoDrivas, Theodore GTheodore GDrivasHennessy, LauraLauraHennessyRaper, AnnaAnnaRaperParenti, IlariaIlariaParentiKaiser, Frank JFrank JKaiserKuechler, AlmaAlmaKuechlerBusk, Øyvind LØyvind LBuskIslam, LilyLilyIslamSiedlik, Jacob AJacob ASiedlikHenderson, Lindsay BLindsay BHendersonJuusola, JaneJaneJuusolaPerson, RichardRichardPersonSchnur, Rhonda ERhonda ESchnurVitobello, AntonioAntonioVitobelloBanka, SiddharthSiddharthBankaBhoj, Elizabeth JElizabeth JBhojStessman, Holly A FHolly A FStessman2024-10-252024-10-252023-03-10https://boris-portal.unibe.ch/handle/20.500.12422/165006Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.en600 - Technology::610 - Medicine & healtharticle10.48350/1798933689794110.1126/sciadv.ade1463