Edited from the 12-17-ST+CM Version

MOL #97998

Supplemental Data

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurological Diseases

Hongjie Yuan, Chian-Ming Low, Olivia A. Moody, Andrew Jenkins, and Stephen F. Traynelis

Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510

Clifton Road, Atlanta GA 30032 (H.Y., A.J., S.F.T.)

Department of Pharmacology and Department of Anaesthesia, Yong Loo Lin School of Medicine, NUS

Graduate School for Integrative Sciences and Engineering, and Neurobiology/Ageing Programme,

National University of Singapore, 28 Medical Drive, S117456 (C-M.L.)

Department of Anesthesiology, Emory University School of Medicine, Rollins Research Center, 1510

Clifton Road, Atlanta GA 30032 (O.A.M., A.J.)

Supplemental Table S1. List of GABA AR subunit mutations identified in neurological disorders

Gene Sex Changes Genotype Location Phenotype Functional Validation Refs GABRA1 p.S326fs328X C del M3 Epi NMD/ERAD 1 GABRA1 M+F p.T20I c.C>T NTD Epi no 2 GABRA1 M+F p.R112Q c.G>A NTD Epi ↓eﬃcacy 3 GABRA1 M+F p.K353delins18X 25 b.p. insertion ICD/intron Epi ER retention→↓expression 4 GABRA1 M+F p.D219N c.G>A NTD Epi impaired kinetics 4 GABRA1 F p.G251S c.G>A NTD/M1 junction Epi no 3 GABRA1 M p.T292I c.C>T M2 IS no 5 GABRA1 M p.K306T c.C>T M2‐3 loop Epi no 3 GABRA1 M+F del(chr5:161,048,671‐161,558,604) del 5q34 Epi no 6 GABRA1 M del(chr5:156.18‐162.63Mb) del 5q33‐5q34 Epi no` 7 GABRA1 M+F p.A322D (A294D) c.C>A M3 Epi reduced current 8,9,10 GABRA1 M + F A/G rs2290732 utr variant 3' SCZ no 11,12 GABRA2 M + F A/G synonymous rs279858 exon 5 ADD / MR no 13,14,15,16 GABRA2 M + F A/G rs490434 3' ADD no 13 GABRA2 M + F A/G rs495818 3' ADD no 14 GABRA2 M + F C/T rs497068 3' ADD no 14 GABRA2 M + F A/G rs531460 3' ADD no 14 GABRA2 M + F C/T rs561779 3' ADD no 14 GABRA2 M + F C/T synonymous rs567926 3'UTR ADD no 13 GABRA2 M+F A/G rs572227 3'UTR ADD no 17 GABRA2 M + F A/G rs572227 3' ADD no 14 GABRA6 M + F C/T rs3219151 3'UTR ADD no 13 GABRA6 C/T rs3219151 3' UTR SCZ no 18 GABRA6 MF p.P385S ICD ADD no 19 GABRB2 M + F A/G rs168697 3' UTR SCZ no 20 GABRB2 M + F A/G rs1816071 Intron SCZ affect isoforms of GABRB2 transcript levels, methylation site 22,23,11 GABRB2 M + F C/T rs1816072 Intron SCZ affect short GABRB2 transcript levels 22 GABRB2 M + F C/T rs2546620 Intron SCZ affect short GABRB2 transcript levels 22 paternally under transmitted minor allele to affected offspring. overlapping GABRB2 M T/G s6556547 Exon 9 SCZ 11 methylation site rs4273008 (G)‐ Epi lower transcriptional activity of GABRB3+ reduced nuclear protein binding rs4906902 (C)‐ affinity. rs7171660 (T)‐ GABRB3 M + F 24 rs20317 (G)‐rs20318 (A)‐rs3212333 (C)

GABRB3 M + F A/G rs2081648 Intron ASD no 25 5' regulatory region (exon GABRB3 M + F A/G rs4906902 Epi, ADD no 21,26 1a) GABRB3 M+F P11S exon 1 Epi abnormal glycosylation 27 GABRB3 M+F S15F exon 1 Epi abnormal glycosylation 27 GABRB3 M+F G32R exon 2 Epi abnormal glycosylation 27 GABRD E177A NTD Epi ↓efficacy 28 GABRD R220H TND Epi ↓efficacy 28 GABRG1 M + F A/G rs1497568 3'UTR ADD no 15 GABRG1 M C/T rs17639557 Promoter ADD no 15 GABRG1 M + F C/T rs6447493 3'UTR ADD no 15 GABRG1 M + F C/T rs976156 Exon 3 ADD no 15 GABRG2 M + F C/T rs183294 5' region SCZ no 29 GABRG2 M + F synonymous (Asn196Asn) rs211037 exon Epi no 30 GABRG2 p.R82Q NTD, gb interface Epi ↓oligomerizaon→ER retenon→↓expression 31 GABRG2 p.K328M M2‐3 loop Epi ↓efficacy 32 GABRG2 p.R177G NTD Epi impaired kinetics 33 GABRG2 p.Q390X ICD Epi ↓oligomerizaon→ER retenon→↓expression 34 GABRG2 p.Q40X NTD Epi ↓oligomerizaon→ER retenon→↓expression 35 GABRG2 p.Q429X M3 Epi ↓oligomerizaon→ER retenon→↓expression 36 GABRG2 IVS6+2T→G intron 6 Epi no 37 GABRP M + F A/G rs7736504 SCZ GABRA1 affected transcript levels of other 5q GABA‐AR genes. 20

ADD: addiction, ASD: autism spectrum disorder, Epi: epilepsy, IS: infantile spasms, MR: mental retardation, SCZ: schizophrenia

References 1. Maljevic, et al., (2006). Annals Neurol 59, 983‐987 2. Klassen (2011) Cell 145, 1036 3. Carvill (2014) Neurology 82, 1245 4. Lachance‐Touchette (2011) Eur J Neurosci 34, 237 5. Epi4K (2013) Nature 501:217‐221 6. Olson et al., (2014) Ann Neurol. 75:943‐58 7. Mefford et al., (2011) Ann Neurol. 70:974‐85 8. Cossette et al., (2002). Nat Genet 31, 184‐189 9. Fisher (2004) Neuropharmacology 46: 629 10. Krampfl et al., (2011) Eur J Neurosci 22 :10‐20 11. Pun et al., (2011). Mol Psychiatry 16, 557‐568 12. Zhou et al., (2012). CNS Neurosci Ther 18(7):566‐72 13. Li et al., (2014). Neuropsychopharmacology 39, 907‐918 14. Edenberg et al., (2004). Am J Hum Genet 74, 705‐714 15. Enoch et al., (2009). Neuropsychopharmacology 34, 1245‐1254 16. Heitzeg et al., (2014). Neuropsychopharmacology 39, 3077‐3086 17. Bierut et al., (2010). PNAS 107, 5082‐5087 18. Gong et al., (2013). Eur Neuropsychopharm 23, 1182‐1189 19. Radel et al., (2005). Arch Gen Psychiatry 62, 47‐55 20. Petryshen et al., (2005). Mol Psychiatry 10, 1074‐1088, 1057 21. Chen et al., (2014). PloS one 9, e102227 22. Zhao et al., (2006). Mol Psychiatry 11, 1092‐1105 23. Lo et al., (2004). Mol Psychiatry 9, 603‐608 24. Urak et al., (2006). Hum Mol Genet 15, 2533‐2541 25. Kim et al., (2006). Neuropsychobiology 54, 160‐165 26. Pernhorst et al., (2011). J Neuropathol Exp Neurol 70, 1080‐1088 27. Tanaka et al., (2008). Am J Hum Genet 82, 1249‐1261 28. Dibbens et al., (2004). Hum Mol Genet 13, 1315‐1319 29. Zai et al., (2009). Schizophr Res 114, 33‐38 30. Balan et al., (2013). Pharmacogenet Genomics 23, 605‐610 31. Wallace et al., (2001). Nat Genet 28, 49‐52 32. Baulac et al., (2001). Nat Genet 28, 46‐48 33. Audenaert et al., (2006). Neurology 67, 687‐690 34. Harkin etal., (2002). Am J Hum Genet 70, 530‐536 35. Huang et al., (2012). Neurobiol Dis 48, 115‐123 36. Sun et al., (2008). Chin J Med Genet 25, 611‐615 37. Kananura et al., (2002). Arch Neurol 59, 1137‐1141 Supplemental Table S2. List of NMDAR subunit mutations identified in neurological disorders Gene Sex Age‐at‐Onset (yrs) Changes Genotype location MAF Origin Phenotype Functional validation Refs GRIN1 p.Arg306Gln c.G>A ATD SCZ no 1 GRIN1 p.Ala349Ser c.G>T ATD SCZ no 1 GRIN1 p.Thr419Ala c.A>G LBD (S1) ASD no 1 GRIN1 M p.Asp552Glu c.C>G S1‐M1 link DNM Epi, ID no 23 GRIN1 M p.Pro557Arg c.C>G S1‐M1 link DNM ID no 2 GRIN1 M NA p.Ser560dup ins AGC S1‐M1 link DNM ID,epi Yes, current↓ 3 GRIN1 M p.Met641Ile c.G>A M3 DNM Epi, ID no 23 GRIN1 p.Tyr647Ser c.A>C M3 DNM ID, IS no 4 GRIN1 M p.Asn650Lys c.C>G M3 DNM Epi, ID no 23 GRIN1 F NA p.Glu662Lys c.G>A M3‐S2 link DNM ID Yes, Gly, Mg 3 GRIN1 F p.Gly815Arg c.G>C M4 DNM Epi, ID no 23 GRIN2A F 3.5 p.Met1Thr c.T>C ATD ID, Epi, LD no 5 GRIN2A p.Pro31Thr c.C>A ATD Epi, no 6 GRIN2A M 4 p.Pro31Serfs*107 c.90delTins (T)2 ATD Trans Epi, no 6 GRIN2A M 6 p.Pro79Arg c.C>G ATD Trans Epi, ADHD, LD no 6 GRIN2A M 2.5 p.Phe139Ile fs*15 c.1007 + 1 G>A ATD DD, ID, Epi, LD no 5 GRIN2A p. Thr143Ile c.C>T ATD ASD no 1 GRIN2A M na p.Phe183Ile c.T>A ATD Trans DD, Epi, no 6 GRIN2A M 4 p.Ile184Ser c.T>G ATD DNM DD, Epi, LD no 7 GRIN2A p.Thr189Asn c.C>A ATD ASD no 1 GRIN2A M 3.5 p.Trp198* c.G>A ATD DD, Epi no 6 GRIN2A M p.Gln218* c.C>T ATD Trans MR, Epi no 8 GRIN2A M 3 p.Cys231Tyr c.G>A ATD Trans ID, Epi, motor delay, LD no 6 GRIN2A M 5.5 p.Ala243Val c.C>T ATD Epi, learning problems Yes, Zinc↓ 6 GRIN2A F 8.3 p.Ala290Val c.C>T ATD Epi, no 6 GRIN2A M 10 p.Gly295Ser c.G>A ATD < 0.01 Epi, no 7 GRIN2A p.Ala302Thr c.G>A ATD Trans ID no 3 GRIN2A F 4 p.Leu334* c.T>A ATD Trans Epi, LD no 6 GRIN2A F 7 p.Arg370Trp c.C>T ATD Epi no 6 GRIN2A M 4 p.Val375fs c.1123‐2A>G ATD Trans Epi, LD no 7 GRIN2A F 4 p.Cys436Arg c.T>C LBD (S1) DNM Epi, LD no 6 GRIN2A p.Val452Met c.G>A LBD (S1) < 0.01 SCZ; 2 pts no 1 GRIN2A F 4 p.Gly483Arg c.G>A LBD (S1) Trans Epi, DD, LD no 7 GRIN2A F 4 p.Arg504Trp c.C>T LBD (S1) Trans DD, Epi, ADHD features no 7 GRIN2A M4 p. Val506Ala LBD (S1) Trans ID, Epi no 9 GRIN2A F 2 p.Arg518His c.G>A LBD (S1) Epi, LD Yes, tau,Po↑ 7,22 GRIN2A M 2 p.Val529Trpfs*22 c.1585delG LBD (S1) Trans ID, Epi, motor delay, LD no 6 GRIN2A F 6.5 p.Thr531Met c.C>T LBD (S1) Trans DD, ID, Epi, LD Yes, Po↑ 5 GRIN2A M 4 p.Ser547del c.1637_1639delctt S1‐M1 link ID, Epi, motor delay, LD no 6 GRIN2A F 6 p.Ala548Thr c.G>A S1‐M1 link DNM DD, Epi, ADHD features no 7 GRIN2A F 0.25 p.Pro552Arg c.C>G S1‐M1 link DNM ID, Epi no 10 GRIN2A p.Val559Met c.G>A M1 Trans ID no 3 GRIN2A p.Arg586Lys c.G>A M1‐M2 link Epi no 8 GRIN2A F p.Asn615Lys c.C>A M2 DNM MR, Epi Yes Mg↓ 8 GRIN2A F 0 p.Leu649Val c.C>G M3 DNM ID, Epi no 10 GRIN2A M 2 p.Phe652Val c.T>G M3 DNM Epi,LD, ASD features Yes, Po↑ 7 GRIN2A M 4 p.Lys669Asn c.G>T LBD (S2) DNM Epi, LD no 7 GRIN2A M 3.5 p.Arg681* c.C>T LBD (S2) Trans Epi, learning disability, LD no 6 GRIN2A F 2.5 p.Ile694Thr c.T>C LBD (S2) DNM DD, Epi, LD, ADHD features no 7 GRIN2A M 8 p.Pro699Ser c.C>T LBD (S2) DNM Epi no 6 GRIN2A F 8 p.Met705Val c.A>G LBD (S2) Trans DD, Epi no 6 GRIN2A M 4.5 p.Glu714Lys c.G>A LBD (S2) Epi, Attention deficit no 6 GRIN2A F 2.5 p.Ala716Thr c.G>A LBD (S2) Trans ID, DD, Epi, LD no 7 GRIN2A F 6 p.Ala727Thr c.G>A LBD (S2) Epi no 6 GRIN2A F 6 p.Asp731Asn c.G>A LBD (S2) Trans Epi no 7 GRIN2A F 6 p.Val734Leu c.G>C LBD (S2) Trans Epi, verbal dypraxia no 6 GRIN2A M 2.6 p.Lys772Glu c.A>G LBD (S2) Epi, learning/reading problems no 6 GRIN2A M 4 p.Leu779Serfs*5 c.2334_2338delcttgc LBD (S2) Trans Epi, Attention deficit no 6 GRIN2A p.Leu812Met c.C>A S2‐M4 link DNM ID, Epi Yes 11,21 GRIN2A M 4.8 p.Ile814Thr c.T>C S2‐M4 link Trans Epi no 6 GRIN2A Fp. Met817Val c.A>G M4 DNM Epi no 12 GRIN2A p.Val852Met c.G>A CTD < 0.01 SCZ no 1 GRIN2A M 7 p.Ile904Phe c.A>T CTD Trans Epi, motor delay, LD no 6 GRIN2A p.Ala922Val c.C>T CTD ASD no 1 GRIN2A M 1 p.Asp933Asn c.G>A CTD DNM Epi, LD, ADHD features no 7 GRIN2A M2 p.Tyr943* c.C>G CTD Trans MR, Epi no 6 GRIN2A p.Val967Leu c.G>C CTD < 0.01 ID; epi no 3,6 GRIN2A p.Ala968Thr c.G>A CTD DNM SCZ no 1 GRIN2A M na p.Asn976Ser c.A>G CTD Epi, Dyslexia no 6 GRIN2A p.Val998Met c.G>A CTD SCZ no 1 GRIN2A p.Thr1064Ala c.A>G CTD Trans ID, Epi; SCZ no 1,6,8 GRIN2A p.Asn1076Lys c.C>G CTD < 0.01 ND ID, Epi no 6,8 GRIN2A p.Arg1159Pro c.G>C CTD < 0.01 SCZ no 1 GRIN2A p.Thr1229Ser c.A>T CTD SCZ no 1 GRIN2A M 3 p.Asp1251Asn c.G>A CTD Trans Epi, LD no 7 GRIN2A p.Ala1276Gly c.C>G CTD < 0.01 Epi no 1,6,7 GRIN2A M p.Ile1295Thr c.T>C CTD DNM SCZ no 13 GRIN2A M 4 p.Tyr1387* c.C>A CTD DD, Epi, ASD and ADHD features no 7 GRIN2B p.Val18Ile c.G>A ATD SCZ no 1 GRIN2B p.Ser34 ins Gly ins ACG ATD ASD, ID no 14 GRIN2B p.Ile50NAsn c.T>A ATD SCZ no 1 GRIN2B M c.411 + 1 G>A c.411 + 1 G>A ATD DNM MR no 8 GRIN2B F p.Thr268SfsX15 c.803_804delCA ATD DNM ID, ADHD no 8 GRIN2B p.Ala271Val c.C>T ATD < 0.01 SCZ no 1 GRIN2B p.Leu362Met c.C>A ATD SCZ no 1,15 GRIN2B p. Glu413Gly c.A>G LBD (S1) ID Yes 16 GRIN2B M p.Cys456Tyr c.G>A LBD (S1) ASD no 14 GRIN2B p.Cys461Phe c.G>T LBD (S1) DNM ID, LGS, austistic feature no 4 GRIN2B F 1 p.Arg540His c.G>A LBD (S1) DNM ID, Epi Yes, Mg↓, Glu↑ 17 GRIN2B M 0 p.Pro553Leu c.C>T S1‐M1 link DNM ID no 10 GRIN2B F p.Trp559* M1 ASD, ID no 14 GRIN2B p. F577E578del c.1729‐1734 delTTTGAG M1 ID no 16 GRIN2B p.Ala590Thr c.G>A M1‐M2 link < 0.01 Trans ID no 8 GRIN2B F 0.2 p.Asn615Ile c.A>T M2 DNM IS Yes, Mg↓ 17 GRIN2B M 0.5 p.Val618Gly c.T>G M2 DNM IS Yes, Mg↓ 17 GRIN2B F 2 p.Ala636Pro c.G>C M3 ID; ADHD no 18 GRIN2B M p.Arg682Cys c.C>T LBD (S2) DNM ID Yes, Glu, Gly↑X2 8 GRIN2B M 0.1 c. 2011‐5_2011‐4delTC c. 2011‐5_2011‐4delTC LBD (S2) Trans ID, Epi no 17 GRIN2B p. Gln711* c.G>A LBD (S2) ASD no 19 GRIN2B F c.2172‐2A>G c.2172‐2A>G LBD (S2) ASD, ID no 14 GRIN2B F c.2360‐2A>G c.2360‐2A>G LBD (S2) DNM ID no 8 GRIN2B p.Met789Lys c.T>A LBD (S2) ASD no 15 GRIN2B p.Leu825Val c.T>G M4 DNM ASD no 1,15 GRIN2B p.Gln1014Arg c.A>G CTD SCZ no 1,15 GRIN2B p.Gly1026Ser c.G>A CTD ASD no 1 GRIN2B p.Ala1267Ser c.G>T CTD Trans ID no 8 GRIN2B p.K1293R c.A>G CTD DNM AD no 20 GRIN2B p.Met1331Ile c.G>A CTD < 0.01 ID no 8 GRIN2B p.Asn1352del c.4056_4058delCAA CTD SCZ no 1 GRIN2B p.Ser1415Leu c.C>T CTD ASD no 1 GRIN2B p.Leu1424Phe c.C>T CTD SCZ no 1,15 GRIN2B p.Ser1452Phe c.C>T CTD SCZ no 1 GRIN2C p.Ala8Thr c.G>A ATD < 0.01 NT ID no 2 GRIN2C p.Trp18* c.G>A ATD ASD no 1,15 GRIN2C p.Leu65Phe c.C>T ATD < 0.01 NT ID no 3 GRIN2C p.Ala166Val c.C>T ATD SCZ no 1 GRIN2C p.G244_L245insP c.733_734insCCG ATD ASD no 1 GRIN2C p.Gly351Val c.G>T ATD Trans ID no 3 GRIN2C p.Val490Ile c.G>A LBD (S1) < 0.01 NT ID no 3 GRIN2C p.Ala641Thr c.G>A M3 SCZ no 1 GRIN2C p.Ala649Thr c.G>A M3 Trans ID no 2 GRIN2C p.Arg679Cys c.C>T LBD (S2) SCZ no 1 GRIN2C p.Ile863Thr c.T>C CTD ASD no 1 GRIN2C p.Pro877Ser c.C>T CTD < 0.01 Trans ASD; ID no 1,3 GRIN2C p.Ser911Arg c.A>C CTD Trans ID no 3 GRIN2C p.Ser911Ile c.G>T CTD SCZ no 1 GRIN2C p.Ser989Pro c.T>C CTD < 0.01 SCZ no 1 GRIN2C p.Ser992Phe c.C>T CTD Trans ID no 3 GRIN2C p.Ser995Leu c.C>T CTD ASD, SCZ no 1 GRIN2C p.E1048_L1049insPPE c.3145_3146insCCCCGGAGC CTD NT ID no 3 GRIN2C p.Gly1180Arg c.G>A CTD 0.0212 Trans ID no 3 GRIN2C p.Gly1180Arg c.G>C CTD ASD, SCZ no 1 GRIN2C p.His1187_Gly1193del c.3560_3580delACAGGGGCAGGACTCTGGGG CTD NT ID no 3 GRIN2C p.His1187_Gly1194del c.3560_3580del CTD SCZ no 1 GRIN2C p.Thr1196Ile c.C>T CTD < 0.01 SCZ no 1 GRIN2C p.Arg1209Ser c.G T CTD 0.2895 NT ID no 3 GRIN2D p.Arg237Leu c.G>T ATD SCZ no 1 GRIN2D p.Leu466Val c.C>G LBD (S1) SCZ no 1 GRIN2D p.Met592Leu c.A>C M1 ASD no 1 GRIN2D p.Met733Val c.A>G LBD (S2) SCZ no 1 GRIN2D p.Arg872His c.G>A CTD SCZ no 1 GRIN2D p.Met883Ile c.G>A CTD SCZ no 1 GRIN2D p.Ala901Ile c.G2701A + c.C2702T CTD SCZ no 1 GRIN2D p.Ala922Val c.C>T CTD < 0.01 SCZ no 1 GRIN2D p.Ala926Thr c.G>A CTD ASD no 1 GRIN2D p.Ala982Pro c.G>C CTD SCZ no 1 GRIN2D p.Gly1317Ser c.G>A CTD 0.0124 ASD; SCZ no 1

ADHD: Attention Deficit Hyperactivity Disorder; ASD: Autism Spectrum Disorder; DD: Developmental Delay; Epi: Epilepsy; ID: intellectual disability; IS: Infantile Spasms; LD: language delay; MR: Mental Retardation; SCZ: Schizophrenia DNM: De Novo Mutation; Trans: Transmitted MAF: global Minor Allele Frequency; from http://www.ncbi.nlm.nih.gov/projects/SNP/

References 1. Tarabeux et al., (2011). Transl Psychiatry 1:e55 2. Redin et al., (2014). J Med Genet 51:724‐736 3. Hamdan et al., (2011). Am J Hum Genet 88(3):306‐16 4. Epi4K and EPGP Investigators (2013). Nature 501:217‐221 5. Carvill et al., (2013). Nat Genet 45:1073‐1076 6. Lemke et al., (2013). Nat Genet 45:1067‐1072 7. Lesca et al., (2013). Nat Genet 45:1061‐1066 8. Endele et al., (2010). Nature Genet 42(11):1021‐1026 9. DeVries and Patel, (2013). Pediatr Neurol 49:482‐485 10. de Ligt et al., (2012). N Engl J Med 367:1921–1929 11. Yuan et al., (2014). Nat Commun 5:3251 12. Venkateswaran et al., (2014). Epilepsia 55:e75‐79 13. Fromer et al., (2014). Nature 506:179‐184 14. O'Roak et al., (2012). Science 338:1619‐1622 15. Myers et al., (2011). PLOS Genet 7(2):e1001318 16. Adams et al., (2014). Mol Genet Metab 113:161‐170 17. Lemke et al, (2014). Ann Neurol 75:147‐154 18. Freunscht et al., (2013). Behav and Brain Func 9:20 19. Kenny et al., (2014). Mol Psychiatry 19:872‐879 20. Andreoli et al., (2014). J Neural Transm 121:533‐542 21. Pierson et al., (2014). Ann Clin Transl Neurol 1:190‐198 22. Conroy et al., (2014). Epilepsia 55:858‐865 23. Ohba et al., (2015). Epilepsia doi: 10.1111/epi.12987 Supplemental Table S3. List of AMPA-R subunit mutations identified in neurological disorders

Gene Sex Age-at-Onset (yrs) Changes Genotype location MAF* Origin Phenotype Functional validation Refs GRIA1 p.Cys101Ser c.G->C ATD Trans ID No 1 GRIA1 p.Ala636Thr c.1906G->A M3 ID No 7 GRIA2 p.Asp781His c.G->C S2-M4 Trans ID No 1 a fusion transcript of ID; severe speech GRIA2 M 3yo deleted exons 1 & 2 DNM No 5 GLRB and GRIA2 delay Yes,  homo- & di-meric GRIA3 M&F p.Arg450Gln c.G1642A LBD (S1) - Trans moderate MR 2 desen; deactiv moderate MR, Yes, no homomeric current,  GRIA3 M p.Arg631Ser c.C->A M2-M3 link <0.01^ Trans 2 aesthenic body habitus heteromeric desen,  deactiv Yes, no homomeric current,  GRIA3 M p.Met706Asp c.T->C LBD (S2) <0.01^ MR 2 heteromeric desen,  deactiv

moderate MR,Epi, autistic Yes, ER protein misfolding;  GRIA3 M p.Gly833Arg c.G->A M4 <0.01^ Trans 2 behavior heteromeric desen, deactiv

GRIA3 M GRIA3del del Xq25 entire GRIA3 moderate MR No 2 GRIA3 dupl exon 1-12fs - Trans MR No 3 GRIA3 dupl exon 2-12fs - Trans MR No 3 GRIA3 dupl exon 3-12fs - Trans MR No 3 GRIA3 p.Gly756Cys c.T->G S2 Trans ID No 1 GRIA3 M dupl 970bp del GRIA3 - Trans ID, Epi No 4 severe ID with autistic GRIA3 M p.Gly630Arg c.1888G > C M2-M3 link <0.01^ Trans No 6 features, epi

Epi: Epilepsy; ID: intellectual disability;MR: Mental Retardation DNM: De Novo Mutation; Trans: Transmitted * http://www.ncbi.nlm.nih.gov/projects/SNP/ ^ http://omim.org/entry/305915 MAF: global Minor Allele Frequency

References 1. Hamdan et al., (2011). Am J Hum Genet 88:306-316 2. Wu et al., (2007). Proc Natl Acad Sci (USA) 104:18163–18168 3. Bonnet C. et al., (2009). Am J Med Genet Part A 149A:1280–1289 4. Bonnet C. et al., (2012). Hum Mutat 33:355–358 5. Hackmann et al., (2013). Eur J Hum Genet 21:112–114 6. Philips et al., (2014). Orphanet J Rare Dis 9:49 7. de Ligt et al., (2012). N Engl J Med 367:1921-1929 Supplemental Table S4. List of KA-R subunit mutations identified in neurological disorders Gene Sex Age-at-Onset (yrs) Changes Genotype location MAF Origin Phenotype Functional validation Refs GRIK1 p.Leu902Ser T->C CTD ID No 1 GRIK2 p.Met867Ile c.G2894A CTD 0.0066* Trans ASD Yes 2,3,4 GRIK2 M&F del exon 7 & exon 8 distal ATD + LBD (S1) - MR Yes, Loss of function 8 GRIK3 F 6yo 2.6-Mb microdeletion in 1p34.3 del GluK3 - DNM MR No 9 GRIK3 p.Asn750Ile A->T S2 Trans ID No 1 Yes, mRNA stability; hipp GRIK4 indel of 14 bp (-/AGGGGAGGGGCGGG) rs6144536 3'UTR - BP activity, protein 5,6,7 expression GRIK4 p.Gln680Arg A->G M3-S2 Trans ID No 1 GRIK4 p.Val528Ile G->A S1-M1 link ID No 1 GRIK5 p.Arg323Cys C->T ATD Trans ID No 1 GRIK5 p.Ala581Val C->T M1-M2 Trans ID No 1 GRIK5 p.Arg582His G->A M1-M2 Trans ID No 1 GRIK5 p.Arg832Met G->T CTD ID No 1

ID: intellectual disability; ASD: Autistic Syndrome Disorder; BP: Bipolar Disorder; MR: Mental Retardation DNM: De Novo Mutation; Trans: Transmitted UTR: Untranslated region * http://www.ncbi.nlm.nih.gov/projects/SNP/ MAF: global Minor Allele Frequency

References 1. Hamdan et al., (2011). Am J Hum Genet 88:306-316 2. Jamain et al., (2002) Mol Psychiatry 7:302-310 3. Strutz-Seebohm et al., (2006). Cell Physiol Biochem 18:287-294 4. Han Y et al., (2010). Biochemistry 49:9207–9216 5. Pickard et al., (2008). Proc Natl Acad Sci (USA) 105:14940-14945 6. Whalley et al., (2009) Mol Psychiatry 14:467-468 7. Knight et al., (2012) Am J Med Genet B Neuropsychiatr Genet 159B:21-29 8. Motazacker et al., (2007). Am J Hum Genet 81:792-798 9. Takenouchi et al., (2013). Am J Med Genet 164A:456-460 Supplemental Table S5. List of Delta-R subunit mutations identified in neurological disorders Gene Sex Age-at-Onset (yrs) Changes Genotype location MAF Origin Phenotype Functional validation Refs GRID2 p.Thr68Met C->T ATD ID No 1 GRID2 p.Val490Ile G->A S1 ID No 1 GRID2 del exon 2 ATD ATX/ASD Yes 2 GRID2 del exon 4 ATD ATX/ASD No 3

ID: Intellectual Disorder; ATX: Ataxia; ASD: Autistic Syndrome Disorder

References 1. Hamdan et al., (2011). Am J Hum Genet 88:306-316 2. Hills et al., (2013). Neurology 81:1378-1386 3. Utine et al., (2013). J Child Neurol 28:926-932