A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

Heather E. Olson (1) , Nolwenn Jean-Marçais (2, 3) , Edward Yang (4) , Delphine Héron (5, 5) , Katrina Tatton-Brown , Paul van Der Zwaag (6) , Emilia Bijlsma (7) , Bryan Krock (8) , E. Backer , Erik-Jan Kamsteeg , Margje Sinnema , Margot R.F. Reijnders , David Bearden , Amber Begtrup (9) , Aida Telegrafi (9) , Roelineke Lunsing , Lydie Burglen (10, 11) , Gaetan Lesca (12, 13) , Megan T Cho (9) , Lacey Smith , Beth Sheidley , Christelle Moufawad El Achkar , Phillip Pearl (4) , Annapurna Poduri , Cara Skraban , Jennifer Tarpinian , Addie I. Nesbitt (14) , Dietje Fransen van de Putte , Claudia A.L. Ruivenkamp (15) , Patrick Rump , Nicolas Chatron (13, 12) , Isabelle Sabatier (16) , Julitta de Bellescize (17) , Laurent Guibaud (18) , David Sweetser , Jessica Waxler , Klaas Wierenga , - Ddd Study , Jean Donadieu (10) , Vinodh Narayanan , Keri Ramsey , - C4rcd Research Group , Caroline Nava (5, 19) , Jean-Baptiste Rivière (20, 3) , Antonio Vitobello (20, 3) , Frederic Tran Mau-Them (20, 3) , Christophe Philippe (20, 3) , Ange-Line Bruel (20, 3) , Yannis Duffourd (3, 20) , Laurel Thomas (21) , Stefan H. Lelieveld (22, 23) , Janneke Schuurs-Hoeijmakers (22) , Han G. Brunner (22, 24) , Boris Keren (5, 19) , Julien Thevenon (2, 3, 20) , Laurence Faivre (2, 3, 20) , Gary Thomas (25) , Christel Thauvin-Robinet (2, 3, 20)

1 Department of Neurology, Children's Hospital [Boston]
2 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
3 FHU TRANSLAD (CHU de Dijon)
4 Boston Children's Hospital
5 CHU Pitié-Salpêtrière [AP-HP]
6 UMCG - University Medical Center Groningen [Groningen]
7 Department of Clinical Genetics (Leiden University Medical Center)
8 CHOP - Children’s Hospital of Philadelphia
9 GeneDx [Gaithersburg, MD, USA]
10 CHU Trousseau [APHP]
11 GRC ConCer-LD
12 Service de Génétique [HCL Groupement Hospitalier Est]
13 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
14 Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA]
15 Department of Clinical Genetics [Leiden, the Netherlands]
16 Service de Neurologie Pédiatrique [CHU Lyon]
17 Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon]
18 Service de Radiologie [Hôpital Femme Mère Enfant - HCL]
19 ICM - Institut du Cerveau = Paris Brain Institute
20 Equipe GAD (LNC - U1231)
21 Department of Microbiology and Molecular Genetics ( University of Pittsburgh)
22 Department of Human Genetics [Nijmegen]
23 Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands]
24 Donders Institute for Brain, Cognition and Behaviour
25 University of Pittsburgh Cancer Institute

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.

Mots clés: PACS-2; PACS2; cerebellar dysgenesis; epilepsy; intellectual disability

Domaines: Génétique humaine

Heather E. Olson, Nolwenn Jean-Marçais, Edward Yang, Delphine Héron, Katrina Tatton-Brown, et al.. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis. American Journal of Human Genetics, 2018, 102 (5), pp.995-1007. ⟨10.1016/j.ajhg.2018.03.005⟩. ⟨hal-02064909⟩