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RESEARCH PRODUCT
A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
Heather OlsonNolwenn Jean-marçaisEdward YangDelphine HéronKatrina Tatton-brownPaul Van Der ZwaagEmilia BijlsmaBryan KrockE. BackerErik-jan KamsteegMargje SinnemaMargot R.f. ReijndersDavid BeardenAmber BegtrupAida TelegrafiRoelineke LunsingLydie BurglenGaetan LescaMegan ChoLacey SmithBeth SheidleyChristelle Moufawad El AchkarPhillip PearlAnnapurna PoduriCara SkrabanJennifer TarpinianAddie NesbittDietje Fransen Van De PutteClaudia A.l. RuivenkampPatrick RumpNicolas ChatronIsabelle SabatierJulitta De BellescizeLaurent GuibaudDavid SweetserJessica WaxlerKlaas Wierenga- Ddd StudyJean DonadieuVinodh NarayananKeri Ramsey- C4rcd Research GroupCaroline NavaJean-baptiste RivièreAntonio VitobelloFrederic Tran Mau-themChristophe PhilippeAnge-line BruelYannis DuffourdLaurel ThomasStefan LelieveldJanneke Schuurs-hoeijmakersHan BrunnerBoris KerenJulien ThevenonLaurence FaivreGary ThomasChristel Thauvin-robinetsubject
Male0301 basic medicinePathologyPACS-2Vesicular Transport ProteinsPHENOTYPEBioinformaticsDISEASESensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]Epilepsy0302 clinical medicineMissense mutationGlobal developmental delayAge of OnsetChildGenetics (clinical)Epileptic encephalopathyAPOPTOSIS3. Good healthcerebellar dysgenesisMutation Missense/geneticsintellectual disabilityChild PreschoolEpilepsy GeneralizedFemalePACS2CLINICAL EPILEPSYmedicine.medical_specialtyHeterozygoteGeneralized/geneticsPROTEINSGenetic counselingMutation MissenseMissense/geneticsNeonatal onsetBiologyDIAGNOSISVesicular Transport Proteins/geneticsFacial dysmorphism03 medical and health sciencesDysgenesisAll institutes and research themes of the Radboud University Medical CenterCerebellar DiseasesReportMENDELIAN DISORDERSGeneticsmedicineHumansGeneralized epilepsyPreschoolNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Cerebellar Diseases/geneticsbusiness.industryMUTATIONSInfant NewbornCorrectionInfantFaciesNewbornmedicine.disease030104 developmental biology[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human geneticsMutationepilepsyAutismbusinessEpilepsy Generalized/genetics030217 neurology & neurosurgerydescription
International audience; Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
year | journal | country | edition | language |
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2018-05-03 |