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

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A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis Heather E. Olson, Nolwenn Jean-Marçais, Edward Yang, Delphine Heron, Katrina Tatton-Brown, Paul A. van der Zwaag, Emilia K. Bijlsma, Bryan L. Krock, E. Backer, Erik-Jan Kamsteeg, Margje Sinnema, Margot R.F. Reijnders, David Bearden, Amber Begtrup, Aida Telegrafi, Roelineke J. Lunsing, Lydie Burglen, Gaetan Lesca, Megan T. Cho, Lacey A. Smith, Beth R. Sheidley, Christelle Moufawad El Achkar, Phillip L. Pearl, Annapurna Poduri, Cara M. Skraban, Jennifer Tarpinian, Addie I. Nesbitt, Dietje E. Fransen van de Putte, Claudia A.L. Ruivenkamp, Patrick Rump, Nicolas Chatron, Isabelle Sabatier, Julitta De Bellescize, Laurent Guibaud, David A. Sweetser, Jessica L. Waxler, Klaas J. Wierenga, Jean Donadieu, Vinodh Narayanan, Keri M. Ramsey, Caroline Nava, Jean-Baptiste Rivière, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Ange-Line Bruel, Yannis Duffourd, Laurel Thomas, Stefan H. Lelieveld, Janneke Schuurs-Hoeijmakers, Han G. Brunner, Boris Keren, Julien Thevenon, Laurence Faivre, Gary Thomas, Christel Thauvin- Robinet The American Journal of Human Genetics Volume 102, Issue 5, Pages 995-1007 (May 2018) DOI: 10.1016/j.ajhg.2018.03.005 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Clinical and Imaging Features (A) Pictures of individuals 1 (a, b), 2 (c, d), 3 (e, f), 5 (g, h), 7 (i, j), and 11 (k, l): variable facial dysmorphism. (B) Spectrum of posterior fossa abnormalities in the PACS2 cohort. Sagittal T1 weighted (m–p, u–x), axial T2 weighted (t, y–ab), axial T1 weighted (q, s), and coronal T2 weighted (r) imaging for subject 2 at 5 years of age (m, q), subject 4 at 3 weeks of age (n, r), subject 5 at 7 days of age (o, s), subject 9 at 1 week of age (p, t), subject 10 at 1 month of age (u, y), subject 12 at 3 months of age (v, z), subject 13 at 23 months of age (w, aa), and subject 14 at 2.5 years of age (x, ab). Of 8 subjects with centrally reviewed imaging, there was prominence of the cisterna magna (asterisk in o) in all but subject 13 (w) and widening of the foramen Magendie in all subjects except subject 12 (v). Mild inferior vermian hypoplasia was also evident in subjects 2 (m), 4 (n), 5 (o), and 14 (x). Cerebellar hemisphere dysplasia was present in subjects 2 (q), 4 (r), 5 (s), 12 (z), and 13 (aa) manifest as unusual centrifugal orientation of the folia bilaterally in subjects 2 (q, arrows) and 12 (z, arrows) and on the left side only in subject 5 (s, arrow). Distortion of the foliar pattern was present without centrifugal orientation in subjects 4 (r) and 13 (aa). Subtler foliar distortion was visible in subjects 9 (t) and 14 (ab). The American Journal of Human Genetics 2018 102, 995-1007DOI: (10.1016/j.ajhg.2018.03.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 PACS2 Variant Location (A) Schematic of PACS1 and PACS2 illustrating the proposed domains (ARR, atrophin-1-related region; FBR, furin (cargo)-binding region; MR, middle region; CTR, C-terminal region) and residues important for partner protein binding (AP-1, adaptor protein complex 1; CK2, protein kinase CK2; GGA, Golgi-associated γ-adaptin ear homology domain ARF-interacting protein), with location of PACS1 and PACS2 missense variants responsible for intellectual disability. (B) HCT116 cells, which can be efficiently transfected with plasmids, expressing the indicated proteins were harvested in mRIPA (50 mM Tris-HCl [pH 8.0] plus 1% NP-40, 1% deoxycholate, and 150 mM NaCl) containing proteinase inhibitors (0.5 mM PMSF, 0.1 μM each of aprotinin, E-64, and leupeptin) and phosphatase inhibitors (1 mM Na3VO4 and 20 mM NaF). The FLAG-tagged cargo proteins SIRT1, HDAC1, or TRPV1 were immunoprecipitated with anti-Flag antibody (Sigma #F7425) and co-precipitating HA-tagged PACS2 or PACS2 p.Glu209Lys was detected by western blot using anti-HA antibody (Cell Signaling Technology #3724S) and developed with the Pierce ECL Western Blotting Substrate (ThermoFisher) using a FluorChem E image acquisition system (ProteinSimple). Signals were quantified using the AlphaView image analysis software package (ProteinSimple) and normalized to wild-type PACS2. Data are mean ± standard deviation, n = 4. The American Journal of Human Genetics 2018 102, 995-1007DOI: (10.1016/j.ajhg.2018.03.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions