TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

Supplementary Information for:

TBC1D24 Mutations in a Sibship with Multifocal

Polymyoclonus

Adeline Ngoh1,2*, Jose Bras*3, Rita Guerreiro*3, Amy McTague1,2, Joanne Ng1,2,

Esther Meyer1, W. Kling Chong4, Stewart Boyd5, Linda MacLellan6, Martin

Kirkpatrick7, Manju A Kurian1,2

Supplementary Tables

Supplementary Table 1 ……………………………………………………………… 2

Supplementary Table 2 ……………………………………………………………… 7

Supplementary Figures

Supplementary Figure 1……………………………………………………………... 18

Supplementary Figure 2 …………………………………………………………….. 19

Supplementary References ……………………………………………………….. 20

! 1! Supplementary,Table,1:,,Approach,to,Paediatric,Myoclonus,

Anatomical, Neurophysiological, Examples,of,Conditions/Causes, Associated,Genes,if, DISTRIBUTIO TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment, Origin, findings, to,consider, any, N, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, Options, H,Focal, ! Acute,Or,Insidious" FACTORS, H,Multifocal, ! Progressive,Or, H,Segmental, Static, CORTICAL, Cortical"myoclonus"is" 1. EPILEPTIC,MYOCLONUS" characterised"by1:!" A. Progressive,Myoclonic, EPM1A/, Multifocal" Late" Triggering"factors:" Generalised"tonic"clonic" Piracetam29" " Epilepsy,(EPM)2,,,3, UnverrichtHLundborg, Often" Childhood/Adolescence" !"""Voluntary"action" seizures" Levetiracetam" • Brief"EMG" (i) Unverricht!Lundborg" Disease:"!CSTB4" involving" Insidious"onset" !"Postural" Progressive"ataxia" Sodium"Valproate1" discharges"lasting" disease"EPM1$ EPM1B:"PRICKLE15,6,7!" distal"limbs" Progressive" !"Stimulus"(light," Neurodevelopmental" " less"than"70ms" " EPM2A/B(Lafora, and"face" touch,"noise)" regression" Benzodiazepines" " (ii) Lafora"body"disease$ Body,Disease):" sensitive, Varying"degrees"of" e.g."Clonazepam" • EEG"spikes" (EPM2A/B)$ EPM2A/Laforin8," cognitive"decline" " associated"with" " NHLRC18!" Avoid:" EMG"myoclonic" (iii) Myoclonic"Epilepsy" EPM3:"KCTD79,10,11!" Phenytoin" bursts"and" with"Ragged"Red"Fibres" EPM4:"SCARB212" Carbamazepine" preceding" (MERRF)$ EPM5:"PRICKLE27" Lamotrigine" myoclonus"by"brief" " EPM6:"GOSR213"" Vigabatrin" interval"(20ms"for" (iv) Neuronal"ceroid" EPM7:"KCNC114! hand"muscles"and" lipofuscinosis"(NCL)$ " 35ms"for"calf" " MERRF:"MTTK15,!! muscles)" (v) Dentatorubropallidolu MTTL116,!!MTTH17," " ysian"atrophy"(DRPLA)"$ MTTS118,"MTTS219," " " MTTF20,"MTTP21! • Enhancement"of" (vi) Sialidosis$ " 22 22 early"cortical" $ NCL:"CLN1 ,!CLN2 ,! 22 22 component"of"SSEPs" (vii) Familial" CLN3 ,!CLN5 ,! 22 22 –"giant"SSEPs" encephalopathy"with" CLN6 ,!CLN8 ,! 23 24 " neuroserpin"inclusion" CTSD !MFSD8 ,!! 25 10! • Back"averaging"of" bodies"(FENIB)$ ATP13A2 ,!!KCTD7 ! EEG"time!"locked"to" " 26! myoclonic"jerks"may" " DRPLA:""ATN1 ! disclose"cortical" " 27! origin"of"myoclonic" Sialidosis:"NEU1 ! jerks" 28! " FENIB:,SERPINI1

! 2! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, CORTICAL, Cortical"myoclonus" B. Generalised,Myoclonic, EJM1/JAE1:! Multifocal" Adolescence" Triggering"factors" Seizures, Sodium"valproate42" is"characterised" Epilepsies, EFHC131,32" Insidious"onset" !"EJM:" Usually"normal" Levetiracetam" by1:!" , EJM2:"Linked"to" Static" Photosensitivity, neurodevelopment"or" Lamotrigine"with" " (i) Juvenile"Myoclonic" 15q1433,34" mild" clonazepam"" 30 41 • Brief"EMG" Epilepsy"(EJM) " EJM3:"Linked"to" neurodevelopmental" Avoid :" discharges" (ii) Myoclonic"Absence" 6p2135" impairment, Gabapentin" lasting"less" Epilepsy/Juvenile" EJM4:"Linked"to" Normal"neurological" Phenytoin" than"70ms" Absence"Epilepsy" 5q12!q1436" examination" Carbamazepine" " (JAE)" EJM5:!GABRA137" Vigabatrin" 38" • EEG"spikes" EJM6:"CACNB4 39 associated" EJM7:"GABRD !! with"EMG" EJM8/JAE2:" 40 myoclonic" CLCN2 !! bursts"and" EJM9:"Linked"to" 41" preceding" 2q33!q36 myoclonus"by" " brief"interval" C. Childhood,Myoclonic,Epilepsy, Dravet’s43, Multifocal" Infancy"to"childhood" Photosensitivity" Several"seizure"types"" Dravet’s43, (20ms"for" " syndrome, common"in"Dravet’s" Usually"various"degrees" syndrome, hand"muscles" (i) Severe"myoclonic" SCN1A! syndrome"and" of"neurodevelopmental" Topiramate" and"35ms"for" epilepsy"of"Infancy"!" PCDH19,!GABRA! present"in"some" impairment" Stiripenthol" calf"muscles)" Dravet"Syndrome" GABRG2,!HCN1,! with"Doose’s" Clobazam" " (ii) Myoclonic!"Astatic" STXBP1! syndrome" Levetiracetam" " Epilepsy"Doose" , Ketogenic"diet" " • Enhancement" syndrome" Doose’s " 43, of"early" syndrome Avoid:" cortical" SLC2A1,!SLC6A1! Carbamazepine" component"of" CHD2,!GABRA1,! Lamotrigine" SSEPs"–"giant" GABRG2,!SCN1A,! " 43 SSEPs" SCN1B,!KCNA2! Doose’s " " , syndrome, • Back"averaging" Ketogenic"diet" of"EEG"time!" Usually"refractory" 44 45,46" locked"to" 2. PROGRESSIVE,MYOCLONIC, GOSR2 " Multifocal" Childhood/Adolescence" Triggered"by:" Progressive"ataxia" Similar"to"EPM myoclonic" ATAXIA, Insidious" Voluntary" Intention"tremor" jerks"may" Progressive" movement" Mild"or"no"seizures" disclose" Stress" /cognitive""decline" " cortical"origin" Stimulus"sensitive of"myoclonic" jerks" "

! 3! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, CORTICAL, Cortical"myoclonus" 3. TOXIC/METABOLIC,CAUSES, !" Focal"or" Any"age" ! Usually" Encephalopathy, Remove"toxic"cause" is"characterised" " multifocal, Acute"Onset" stimulus" Negative"myoclonus" Correct"metabolic" by1:!" A. Drugs1,47"" ! Csensitive" may"be"a"feature" disturbance" " ! Levodopa" a (Asterixis)" " • Brief"EMG" ! Bismuth"salicylate" n Symptomatic" discharges" ! Antidepressants" " treatment"for" lasting"less"than" ! Anticonvulsants" b myoclonus"similar" 70ms" (Gabapentin," e to"EPM45" " pregabalin," " • EEG"spikes" lamotrigine," p associated"with" phenytoin)" r EMG"myoclonic" ! Antibiotics" o bursts"and" " g preceding" " r 1,47 myoclonus"by" B. Metabolic , e brief"interval" disturbance/Disorders, s (20ms"for"hand" ! Organ"dysfunction"–" s muscles"and" hepatic,renal" i 35ms"for"calf" ! Electrolyte"or" v muscles)" glycaemic" e" " disturbance" " ! Hyper/" • Enhancement"of" hypothyroidism" early"cortical" ! Storage"disorders" component"of" ! Tay"Sachs"" SSEPs"–"giant" ! Gauchers"Type"3" SSEPs" 4. CENTRAL,NERVOUS,SYSTEM, !" Focal" Any"age."Static"or" Triggered"by" History"of"headache" Surgery"if"possible" 1,47 , " LESION , progressive" voluntary"action Focal"neurological"signs" Symptomatic" • Back"averaging" A. Tumour" treatment"for" of"EEG"time!" B. Vascular"malformation, myoclonus"similar" 46" locked"to" to"EPM 1,47 46" myoclonic"jerks" 5. POSTH,HYPOXIC , !" Multifocal" Any"age"–"Static"or" Triggered"by" Negative"myoclonus" Similar"to"EPM " may"disclose" –,Lance,Adams,Syndrome, improvement"with"time" voluntary"action common" cortical"origin"of" myoclonic"jerks" " !

! 4! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, SUBCORTICAL, No"sign"of" 1. ESSENTIAL,MYOCLONUS,+/H, DYT11:, Multifocal!" Childhood" Dramatic"alleviation" Dystonia" Clonazepam" hyperexcitability"on" DYSTONIA, SGCE48! more"often"in" Insidious" of"myoclonic" Psychiatric"symptoms"–" Bilateral"pallidal"or" EEG"or"SSEP1,45" A. DYT11, " head,"neck" Static" symptoms"with" anxiety,"depression," deep"brain" " B. DYT15, and"upper" alcohol" OCD" stimulation49" Myoclonus"duration" limbs," on"EMG"ranges"from" occasionally"in" 25!300ms45" lower"limbs" " 2. HYPEREKPLEXIA50, GLRA151" Non! Onset"in"infancy" Triggered"by" Hypertonia"(usually" Clonazapam50" A. Genetic, GLRB52" segmental" Insidious" sensory"stimuli"to" transient)" B. Brainstem, GPHN53" Bilateral," Static" the"mantle"area""or" Hypokinesia" encephalitis/ischaemia1,55, ARHGEF953" synchronous" auditory"stimuli" C. Vascular,lesions, SLC6A553,54" involvement"of" without"habituation" D. Multiple,sclerosis56, " facial" (grimacing)," neck"(flexion)," arms" (abduction)" trunk"and"legs" (flexion)" movements" 3. OPSOCLONUSHMYOCLONUS, !" Multifocal" Childhood"onwards" Can"be"triggered"by" Opsoclonus"–" Immuno! SYNDROME57, Insidious/subacute" voluntary"action," involuntary"arrhythmic" modulation57" A. Associated,with, Static" tactile,"visual"or" multi!directional" Steroid"therapy" Neuroblastoma,in,40H,65%, auditory"" saccades" Rituximab" of,children,45,58, stimulus"."" Ataxia" IVIG" , Exacerbated"by" Encephalopathy" stress"or"crying." Irritability"and" behavioural"change" 4. RETICULAR,REFLEX, !" Axially" Any"age" Sensitivity"to"stimuli" Encephalopathy" Clonazepam1,46" MYOCLONUS, localised9" Sub!acute" in"distal"limbs" " A. PostHhypoxic,brain,injury, Non! Static" instead"of"mantle" B. Brain,stem,encephalitis, segmental" area"in"contrast"to" C. Uraemia1, hyperekplexia" 5. PALATAL,MYOCLONUS, " Segmental" Childhood"onwards" H" Ear"clicking/tinnitus" Clonazepam45,46" A. Essential,palatal, involving" Piracetam" myoclonus:,, rhythmic" Carbamazepine" ! Idiopathic, contractions"of" Sodium"valproate" , the"soft"palate" Botulinum"toxin" B. Symptomatic,palatal, injection46" myoclonus:,, Surgical"procedures" ! Vascular" for"ear"clicking46" malformations" ! Brainstem"tumour" ! Multiple"sclerosis" ,

! 5! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, SPINAL, EMG:"myoclonic" 1. SPINAL,SEGMENTAL, !" Segmental" Any"age" Occurs"at"rest" May"have"focal" Clonazepam46" bursts"isolated"to" MYOCLONUS1, Acute"or"insidious" May"or"may"not"be" neurological"signs"" Levetiracetam" one"or"two" A. Syringomyelia, Static"or"progressive" stimulus"sensitive" Carbamazepine" contiguous" B. Myelitis, depending"on"aetiology" Topiramate" myotomes1" C. Spinal,cord,injury, Tetrabenazine" D. Vascular,lesion, E. Neoplasm, F. Spinal,dysraphism59, EMG:"myoclonic" 2. PROPRIOSPINAL,MYOCLONUS1, !" Distributed" Any"age" May"be"triggered"by" " Surgery"for"lesions"if" bursts"lasting"from" A. Idiopathic, over"axial" Acute"or"insidious" eliciting"tendon" appropriate" 50ms"to"4seconds1." B. Cervical,cord,trauma, muscles!"neck," reflexes"or"tactile" Clonazepam" C. Tumour, trunk"and"hips."" stimulus"to"the" Zonisamide46" D. Myelitis, Spares"facial" abdomen" , muscles"unlike" reticular"reflex" myoclonus1" PERIPHERAL, EMG/NCS:"may" 1. NERVE,PLEXUS,,SPINAL, !" Focal" Any"age" " Peripheral"neurological" Botulinum"toxin" show"signs"of" ROOT,OR,PERIPHERAL, Acute/sub!acute" motor"or"sensory"signs" Carbamazepine46" denervation" NERVE,INJURY1, Static" A. Hemifacial,spasm60, !

! 6! Supplementary,Table,2A:,Alternative,candidate,genes,identified,on,whole,exome,sequencing,–,Compound,Heterozygous,Changes,

Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene,exclusion,as, a,candidate,gene, CTBS% NM_004388! c.92_100del! p.Leu31_Leu33del! rs142534762! NA! NA! NA! Chitobiase!is!a!lysosomal! Highest! Observed!variants!in!Exac! glycosidase!involved!in! expression!in! database! c.66_74del! p.Ala26_Leu28del! rs757082869! NA! NA! NA! degradation!of!asparagine# liver,!expressed!in! 1st!change:!!1295! linked!oligosaccharides!on! brain! homozygotes;!7901!allele! glycoproteins!! count;!0.2466!allele! frequency! 2nd!change:!122! homozygotes,!2926!allele! count;!0.09939! LAD1% NM_005558! c.486_488del! p.162_163del! NA! NA! NA! NA! Encodes!a!protein!which!may! Highest! 2nd!change!(c.483_484del)!is! be!an!anchoring!filament! expression!in! observed!variant!on!Exac:!! c.483_484del! p.L161fs! rs552300739! NA! NA! NA! that!is!a!component!of! kidney,!not! 110!homozygotes,!2300! (dbSNP142)!! basement!membranes.!It! expressed!in!brain! allele!count;!0.02257!allele! rs78190062! may!contribute!to!the! frequency! (dbSNP131)! stability!of!the!association!of! the!epithelial!layers!with!the! underlying!mesenchyme.! PTPN23% NM_015466! c.A1748G! p.K583R! rs147293860! 0.897! 0.029! #1.25! Plays!a!role!in!sorting!of! Highest! Both!changes!inherited!from! (possibly! (Damaging)! (Neutral)! endocytic!ubiquitinated! expression!in! father!and!second!change!is! damaging)! cargos!into!multivesicular! ovary,!expressed! predicted!to!be!benign!on!in! c.G3051C! p.Q1017H! rs201017613! 0.001! 0.076! #0.81! bodies!(MVBs)!via!its! in!brain! silico!prediction!websites! (Benign)! (Tolerated)! (Neutral)! interaction!with!the!ESCRT#I! complex!(endosomal!sorting! complex!required!for! transport!I),!and!possibly! also!other!ESCRT!complexes.! May!act!as!a!negative! regulator!of!Ras#mediated! mitogenic!activity.!Plays!a! role!in!ciliogenesis! ! !

! 7! ! !

Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene,exclusion,as, a,candidate,gene, OBSCN% NM_001098623! c.G4785C! p.E1595D! rs185523702! 0.018! 0.291! #1.44! Encodes!a!!protein!belonging! Highest! 1st!change!benign!on!in!silico! (benign)! (tolerated)! (Neutral)! to!the!family!of!giant! expression!in! prediction!websites.! c.G6373T! p.A2125S! rs75280352! 0.844! 0.807! #0.64! sacromeric!signaling!proteins! skeletal!muscle,! Both!changes!are!observed! !(possibly! (tolerated)! (Neutral)! that!includes!titin!and! expressed!in!brain! variants!on!Exac.! damaging)! nebulin,!and!may!have!a!role! 1st!change:!19!homozygotes;! in!the!organization!of! 1644!allele!count;!0.01368! myofibrils!during!assembly! allele!frequency.! and!may!mediate! 2nd!change:!25!homozygotes;! interactions!between!the! 2101!allele!count;!0.02044! sarcoplasmic!reticulum!and! allele!frequency! myofibrils.![provided!by! RefSeq,!Jul!2008].! USH2A% NM_206933! c.G13297T! p.V4433L! rs111033381! 0.00!(benign)! 0.321! #0.38!! Encodes!a!protein!that! Highest! Both!benign!changes!on!in! (tolerated)! (Neutral)! contains!laminin!EGF!motifs,! expression!in! silico!predictive!websites.! c.G1434C! p.E478D! rs35730265! 0.100! 0.155! #1.58! a!pentaxin!domain,!and! testes,!expressed! Both!also!observed!variants! (benign)! (tolerated)! (Neutral)! many!fibronectin!type!III! in!brain! on!Exac.! motifs.!The!protein!is!found! 1st!change:31!homozygotes;! in!the!basement!membrane,! 2329!allele!count,!0.01921! and!may!be!important!in! allele!frequency! development!and! 2nd!change:!23!homozygotes;! homeostasis!of!the!inner!ear! 1437!allele!count;!0.01185! and!retina.!! allele!frequency! MTCH2% NM_014342! c.865_867del! p.289_289del! rs764352276! NA! NA! NA! The!substrate!transported!is! Highest! Both!changes!not!present!on! not!yet!known.!Induces! expression!in! Sanger!Sequencing! c.862_863insGA p.K288fs! NIL! NA! NA! NA! mitochondrial! liver,!expressed!in! CA! depolarization.!! brain!

! 8! ! !

Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene,exclusion, as,a,candidate,gene, PPL% NM_002705! c.A3152T! p.K1051M! rs148151950! 0.846! 0.005! #3.74! Encodes!a!protein!that!is!a! Highest! Both!changes!inherited!from! (Possibly! (Damaging)! (Deleterious)! component!of!desmosomes! expression!in! father! damaging)! and!of!the!epidermal! adipose!tissue,! ! c.A3151G! p.K1051E! rs142943814! 0.611!!! 0.056! #2.61! cornified!envelope!in! expressed!in!brain! (Possibly! (Tolerated)! (Deleterious)! keratinocytes.!The!N# damaging)! terminal!domain!of!this! protein!interacts!with!the! plasma!membrane!and!its!C# terminus!interacts!with! intermediate!filaments.! Through!its!rod!domain,!this! protein!forms!complexes! with!envoplakin.!This!protein! may!serve!as!a!link!between! the!cornified!envelope!and! desmosomes!as!well!as! intermediate!filaments.! AKT1/PKB,!a!protein!kinase! mediating!a!variety!of!cell! growth!and!survival!signaling! processes,!is!reported!to! interact!with!this!protein,! suggesting!a!possible!role!for! this!protein!as!a!localization! signal!in!AKT1#mediated! signaling.!! SHROOM3% NM_020859! c.A1691C! p.E564A! rs76656494! 0.890! 0.004! #2.83! Encodes!a!PDZ#domain# Highest! Both!changes!observed! (possibly! (Damaging)! (deleterious)! containing!protein!that! expression!in! variants!on!Exac.! damaging)! belongs!to!a!family!of! liver,!expressed!in! 1st!change:15!homozygotes,! c.C3035A! p.T1012N! rs147732653! 0.984! 0.001! #3.84! Shroom#related!proteins.! brain! 1398!allele!count,!0.01153! (probably! (Damaging)! (Deleterious)! This!protein!may!be!involved! allele!frequency! damaging)! in!regulating!cell!shape!in! 2nd!change:!2!homozygotes,! certain!tissues.!A!similar! 688!allele!count,!0.01076! protein!in!mice!is!required! allele!frequency! for!proper!neurulation.!!

! 9! Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene, exclusion,as,a,candidate, gene, CMYA5% NM_153610! c.T4231G! p.S1411A! rs188114860! 0.893! 0.021! #1.19! May!serve!as!an!anchoring! Highest! Both!changes!are! (possibly! (Damaging)! (Neutral)! protein!that!mediates!the! expression!in! observed!variants!on! damaging)! subcellular! skeletal!muscle,! Exac! c.A12070G! p.N4024D! rs115059007! 1.000! 0.065! #3.44! compartmentation!of!protein! expressed!in!brain! 1st!change:!7! !(Probably! (Tolerated)! (Deleterious)! kinase!A!(PKA)!via!binding!to! homozygotes,!551!allele! damaging)! PRKAR2A!(By!similarity).!May! count,!0.004695!allele! function!as!a!repressor!of! frequency! calcineurin#mediated! 2nd!change:!40! transcriptional!activity.!May! homozygotes,!2024! attenuate!calcineurin!ability! allele!count,!0.01677! to!induce!slow#fiber!gene! allele!frequency! program!in!muscle!and!may! negatively!modulate!skeletal! muscle!regeneration!(By! similarity).! JADE2% NM_015288! c.G1103T! p.G368V! rs115315395! 0.035! 0.010! #1.60!! Component!of!the!HBO1! Highest! 1st!change!is!observed! (Benign)! (Damaging)! (!Neutral)! complex!which!has!a!histone! expression!in! variant!on!Exac.! c.C1108T! p.R370C! rs137957798! 0.955! 0.005! #2.66! H4#specific!acetyltransferase! digestive!tract,! 1st!change:!14! (Possibly! (Damaging)! (Deleterious)! activity,!a!reduced!activity! expressed!in!brain! homozygotes,!1592! damaging)! toward!histone!H3!and!is! allele!count,!0.01312! responsible!for!the!bulk!of! allele!freq! histone!H4!acetylation!in! vivo.!! FRY% NM_023037! c.T1033C! p.Y345H! NIL! 1.00! 0.00! #4.14! Plays!a!crucial!role!in!the! Highest! 2nd!change!predicted!to! (Probably! (Damaging)! (Deleterious)! structural!integrity!of!mitotic! expression!in! be!benign!on!in!silico! damaging)! centrosomes!and!in!the! heart,!expressed! prediction!sites,!and! c.G3958A! p.A1320T! rs138780336! 0.003!! 0.363! #0.12! maintenance!of!spindle! in!brain! found!in!high!frequency! (benign)! (Tolerated)! (Neutral)! bipolarity!by!promoting!PLK1! on!Exac.!2nd!change:!15! activity!at!the!spindle!poles! homozygotes,!1040! in!early!mitosis.!May!function! allele!count,!0.008616! as!a!scaffold!promoting!the! allele!frequency! interaction!between!AURKA! and!PLK1,!thereby!enhancing! AURKA#mediated!PLK1! phosphorylation.!! C16orf3% NM_001214! c.G178A! p.V60I! rs77382359! 0.00!(benign)! NA! #1.00! In!vivo!function!unknown! Highest! 1st!and!3rd!changes! (Neutral)! expression!in! predicted!to!be!benign! c.T155C! p.I52T! rs55742939! #! NA! H4.67! thyroid,!expressed! on!in!silico!prediction! (Deleterious)! in!brain! sites.!! nd rd c.A154G! p.I52V! rs61118444! #! NA! #1.00! 2 !and!3 !changes!are! (Neutral)! variants!found!on!Exac.! 2nd!change:!5! homozygotes,!509!allele! count,!0.0122!allele! frequency! 3rd!change:!5! homozygotes,!511!allele! count,!0.005029!allele! frequency! ! 10! ! !

Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene, exclusion,as,a,candidate, gene, The!protein!encoded!by!this! Highest! Both!changes!predicted! gene!belongs!to!the!alpha! expression!in! to!be!benign!by!in!silico! subfamily!of!laminin!chains! adrenals,! prediction!websites.! 0.256! 0.125! #1.29! c.G7114A! p.D2372N! rs111653839! and!is!a!major!component!of! expressed!in!brain! (Benign)! (Tolerated)! (Neutral)! basement!membranes.!It!has! a!role!in!maintaining!tissue! integrity!and!development.!! LAMA5% NM_005560! Two!transcript!variants! encoding!different!isoforms! have!been!found!for!this! 0.003!! 0.616! #1.51! c.C6131T! p.A2044V! rs200103455! gene,!but!the!full#length! (Benign)! (Neutral)! (Neutral)! nature!of!one!of!them!has! not!been!determined.!!

EP300% NM_001429! c.T2091G! p.S697R! rs61756764! 0.965!!! 0.007! #1.34! Encodes!the!adenovirus!E1A# Highest! 1st!change!inherited! (Probably! (Damaging)! (Neutral)! associated!cellular!p300! expression!in! from!father!and!2nd! Damaging)! transcriptional!co#activator! blood,!expressed! change!inherited!from! protein!which!functions!as!a! in!brain! mother.! histone!acetyltransferase! ! that!regulates!transcription! Excluded!as!1st!change!is! via!omatin!remodeling!and!is! an!observed!variant!on! important!in!the!processes!of! Exac! cell!proliferation!and! 1st!change:!! differentiation.!It!mediates! 2!homozygotes,!471! cAMP#gene!regulation!by! allele!count,!0.003882! binding!specifically!to! allele!frequency! !c.G6592A! p.G2198R! rs370216095! 0.745! 0.009! #0.57! phosphorylated!CREB! ! (Possibly! (Damaging)! (Neutral)! protein.!This!gene!has!also! The!phenotype!of!our! damaging)! been!identified!as!a!co# sibship!also!does!not! activator!of!HIF1A!(hypoxia# correlate!with!the! inducible!factor!1!alpha),!and! phenotypes!associated! thus!plays!a!role!in!the! with!this!gene#!!Somatic! stimulation!of!hypoxia# colorectal!cancer!and! induced!genes!such!as!VEGF.!! Rubinstein#Taybi! syndrome!2!

! 11! Supplementary,Table,2B:,Alternative,candidate,genes,identified,on,whole,exome,sequencing,–,Homozygous,Changes,

Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene, exclusion,as,a,candidate, gene, KIAA0040% NM_001162895! c.217_225del! p.73_75del! rs150137790! NA! NA! NA! Encodes!an!HLA1#DR11# Highest! Father!has!the!same! restricted!T!cell!epitope!with! expression!in! homozygous!deletion! yet!unknown!function.!! blood,!expressed! Implicated!in!alcohol! in!brain! dependence.!Expression! quantitative!trait!locus! analysis!has!demonstrated! that!the!expression!of!the! KIAA0040!gene!is!associated! with!the!expression!of! multiple!other!genes! involved!in! neurotransmission,!including! several!genes!previously! implicated!in!alcohol! dependence!and!other! psychiatric!disorders,!such!as! DRD2#TTC12,!DRD3,! HTR1B,GRM5!and!OPRD1! Highest! Both!parents!carry!the! G!protein!coupled!olfactory! expression!in! OR2T35% NM_001001827! c.957_958insTG! p.I320_R321delinsX! rs370874670! NA! NA! NA! same!homozygous! receptor! thyroid,!not! insertion!! expressed!in!brain! Has!a!role!in!DNA!binding! Expressed!in!brain! Father!has!the!same! FAM171B% c.129_130insCAG! p.Q43delinsQQ! !rs549897920! NA! NA! NA! NM_177454! genotype!!! % c.147_148insCAG! p.Q49delinsQQ! NIL! NA! NA! NA! GPX1% NM_000581!! c.33_38delGGCG p.Ala12_Ala13del! rs17838762! NA! NA! NA! Encodes!a!member!of!the! Highest! Observed!variant!on! GC! glutathione!peroxidase! expression!in! Exac! family.!Glutathione! breast,!expressed! 15!homozygotes,254! peroxidase!functions!in!the! in!brain! allele!count,!0.0419! detoxification!of!hydrogen! allele!frequency! peroxide,!and!is!one!of!the! most!important!antioxidant! enzymes!in!humans.!! LNP1% NM_001085451 c.194_195insTCCT LNP#1!plays!a!role!in! Highest! Mother!has!the!same! !! AGAAGGCATTCTC synaptogenesis!by!regulating! expression!in! homozygous!insertion! p.H65delinsHPRRHSHED ATGAGGACCAGG NIL! NA! NA! NA! vesicular!transport!or! testes,!expressed! QEFRCRSS! AATTCCGATGCCG localization.! in!brain! ATCGTC! DSPP% NM_014208! Encodes!two!principal! Highest! Observed!variant!on! proteins!of!the!dentin! expression!in! Exac! c.2643_2644insA p.D881delinsDSSD! rs141186173! NA! NA! NA! extracellular!matrix!of!the! testes,!not! 3584!homozygotes;! GTAGTGAC! tooth.!! expressed!in!brain! 11616!allele!counts,! 0.5956!allele!frequency! ! !

! 12! , ! Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene, exclusion,as,a,candidate, gene, HLACDRB5% NM_002125! c.308delC! p.A103fs! NIL! NA! NA! NA! HLA#DRB5!belongs!to!the! Highest! Observed!variant!on! % HLA!class!II!beta!chain! expression!in! Exac! % paralogues.!This!class!II! lung,!expressed!in! 4!homozygotes,!121! molecule!is!a!heterodimer! brain! allele!count,!allele!freq:! consisting!of!an!alpha!(DRA)! 0.002352! c.297delC! p.D99fs! NIL! NA! NA! NA! and!a!beta!(DRB)!chain,!both! Observed!variant!on! anchored!in!the!membrane.! Exac! It!plays!a!central!role!in!the! 16!homozygotes,!1341! immune!system!by! allele!count,!allele!freq:! presenting!peptides!derived! 0.02392! c.293_294insGC! p.E98fs! NIL! NA! NA! NA! from!extracellular!proteins.!! Father!has!the!same! findings! HLACDRB1% NM_002124! c.301delC! p.R101fs! rs67798196! NA! NA! NA! HLA#DRB1!belongs!to!the! Highest! Observed!on!Exac! HLA!class!II!beta!chain! expression!in! 79!homozygotes,!3590! paralogs.!The!class!II! lung,!expressed!in! allele!count;!allele!freq:! molecule!is!a!heterodimer! brain! 0.05936! consisting!of!an!alpha!(DRA)! and!a!beta!chain!(DRB),!both! anchored!in!the!membrane.! It!plays!a!central!role!in!the! immune!system!by! presenting!peptides!derived! from!extracellular!proteins.! Class!II!molecules!are! expressed!in!antigen! presenting!cells!(APC:!B! lymphocytes,!dendritic!cells,! macrophages).!! !

! 13! Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene, exclusion,as,a,candidate, gene, DACH1% NM_004392! c.235_249del! p.79_83del! No! NA! NA! NA! Encodes!an!omatin#associated! Highest! Observed!on!Exac! protein!that!associates!with! expression!in! 2!homozygotes,!15!allele! other!DNA#binding! kidney,! count,!allele!freq:! transcription!factors!to! expressed!in! 0.08427!! regulate!gene!expression!and! brain! ! cell!fate!determination!during! ! development.!The!protein! contains!a!Ski!domain!that!is! highly!conserved!from! Drosophila!to!human.! Expression!of!this!gene!is!lost! in!some!forms!of!metastatic! cancer,!and!is!correlated!with! poor!prognosis.!Multiple! transcript!variants!encoding! different!isoforms!have!been! found!for!this!gene.!! ACIN1% NM_001164815! c.1814_1815insAC p.S605delinsSRS! rs148403158! NA! NA! NA! Encodes!a!nuclear!protein!that! Highest! Observed!on!Exac! GTTC! induces!apoptotic!omatin! expression!in! 5945!homozygotes;! condensation!after!activation! adrenals,! 36308!allele!counts;! by!caspase#3,!without!inducing! expressed!in! 0.3016!allele!freq! DNA!fragmentation.!This! brain! protein!has!also!been!shown!to! be!a!component!of!a!splicing# dependent!multiprotein!exon! junction!complex!(EJC)!that!is! deposited!at!splice!junctions! on!mRNAs,!as!a!consequence! of!pre#mRNA!splicing.!It!may! thus!be!involved!in!mRNA! metabolism!associated!with! splicing.!! ZNF598% NM_178167! c.A40C! p.M14L! rs71384662! 0.620! 1.00! #0.23! This!protein!and!Grb10# Highest! Observed!on!Exac! (possibly! (tolerated)! (Neutral)! interacting!GYF!protein!2!have! expression!in! 2892!homozygotes;! damaging)! been!identified!as!a! skeletal!muscle,! 5784!allele!counts;!1.00! components!of!the!mammalian! expressed!in! allele!freq! 4EHP!(m4EHP)!complex.!The! brain! complex!is!thought!to!function! as!a!translation!repressor!in! embryonic!development.!! FAM83G% NM_001039999 c.2458_2459insAC p.R820delinsHR! rs3071666! NA! NA! NA! May!regulate!the!bone! Highest! Observed!on!Exac! !! C! morphogenetic!proteins!(BMP)! expression!in! 22340!homozygotes;! pathway!.!!T#PCR!revealed!that! adipocytes,!not! 73101!allele!counts;! PAWS1!also!regulated!gene! expressed!in! allele!frequency:!0.6077! expression!independently!of! brain! BMP!signaling.! ! !

! 14! Gene% Gene,reference! DNA,change! Protein,change! Known,rs,No.! PolyphenH2! SIFT! PROVEAN! Gene,function! Expression! Reason,for,gene, exclusion,as,a,candidate, gene! MEX3D% NM_001174118! c.G1525A! p.G509R! rs540664676! 0.971! 0.019! #1.85! RNA!binding!protein,!may!be! Highest! Father!and!both!siblings! (probably! (damaging)! (Neutral)! involved!in!post#transcriptional! expression!in! have!heterozygous! damaging)! Cutoff!0.05! Cutoff!#2.5! regulatory!mechanisms! testes,! change!on!Sanger! expressed!in! Sequencing! brain! DENND1C% NM_024898! c.C1465T! p.R489C! rs35001260! 1.000! 0.001! #2.51! Clathrin!mediated!endocytosis! Highest! Observed!on!Exac! (Q8IV53)% (probably! (damaging)! (deleterious)! is!a!major!mechanism!for! expression!in! 33!homozygotes,!1871! damaging)! internalization!of!proteins!and! lymph,! allele!counts,!allele!freq:! lipids.!Members!of!the! expressed!in! 0.01811! connecdenn!family,!such!as! brain! DENND1C,!function!as!guanine! nucleotide!exchange!factors! (GEFs)!for!the!early!endosomal! small!GTPase!RAB35)!and!bind! to!clathrin!and!clathrin!adaptor! protein#2.! LILRA2% NM_001130917! c.T404C! p.L135S! rs45523736! 0.000! 1.000! 4.81!(Neutral)! !The!LIR!encoded!by!this!gene! Highest! Observed!on!Exac! (benign)! (tolerated)! was!shown!to!be!an!activating! expression!in! 111!homozygotes,!4164! receptor!for!eosinophils!that! blood,! allele!counts,!allele!freq:! elicited!the!release!of!cytotoxic! expressed!in! 0.03431! granule!proteins,!de!novo!lipid! brain! mediator!generation,!and! cytokine!release!through! vesicular!transport.!! SCARF2% NM_153334! c.2304dupC! p.E769fs! rs587606297!! NA! NA! NA! Encodes!a!protein!similar!to! Highest! Observed!on!Exac! SCARF1/SREC#I,!a!scavenger! expression!in! 9!homozygotes,!18!allele! receptor!protein!that!mediates! ovary,! count,!allele!freq:!1! the!binding!and!degradation!of! expressed!in! ! acetylated!low!density! brain! lipoprotein!(Ac#LDL).!This! protein!has!only!little!activity! of!internalizing!modified!low! density!lipoproteins!(LDL),!but! it!can!interact!with!SCARF1! through!its!extracellular! domain.!The!association!of!this! protein!with!SCARF1!is! suppressed!by!the!presence!of! scavenger!ligands.!! FAM58A% NM_152274.3! c.52_53insG! p.(A18Gfs*24)! NIL! NA! NA! NA! The!protein!encoded!by!this! Highest! Observed!on!Exac! gene!contains!a!cyclin#box#fold! expression!in! 2265!homozygotes,! domain!which!suggests!it!may! heart,! 1186!hemizygotes;!5723! have!a!role!in!controlling! expressed!in! allele!count;!allele!freq:! nuclear!cell!division!cycles.!! brain! 0.9988! c.16_17insG! p.(A6Gfs*36)! NIL! NA! NA! NA! Observed!on!Exac! 843!homozygotes;!893! hemizygotes;!2579!allele! count;!allele!freq:!1! ! ! ! ! 15! Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Reason,for,gene, exclusion,as,a,candidate, gene, MEGF9, NM_001080497, c.89_94del, p.30_32del, rs369989873, NA, NA, NA, MEGF9!could!represent!a! Highest! Observed!on!Exac! guidance!molecule,!as!its! expression!in! 503!homozygotes,!1336! expression!pattern!is!present! blood,! allele!count,!allele! during!the!critical!time!points! expressed!in! frequency:!0.7795, in!development.!The! brain, commencing!broad!expression! could!represent!a!migration!or! differentiation!signal,!which! becomes!more!confined!to! specific!structures!during! development.!In!addition!it! could!also!play!a!role!in! maintenance!and!stabilization! processes,!as!it!still!persists!in! adulthood.!In!addition,!MEGF9! could!be!involved!in! myelination,!as!it!is!present!in! the!basement!membranes!of! myelinated!Schwann!cells!in! the!PNS., SYN2% NM_003178! c.246C>A! p.Phe82Leu! rs71624923! 0.000! 0.33! #! This!gene!is!a!member!of!the! Highest! Both!predicted!to!be! NM_133625! (benign)! (tolerated)! synapsin!gene!family.! expression!in! benign!changes!and! c.311C>G! p.Ala104Gly! rs2923856! 0.03!(benign)! 0.54! #! Synapsins!encode!neuronal! brain! found!on!Exac! (tolerated)! phosphoproteins!which! ! associate!with!the!cytoplasmic! 1st!change:!!3! surface!of!synaptic!vesicles.! homozygotes;!6!allele! Family!members!are! counts,!allele!frequency:! characterized!by!common! 1! protein!domains,!and!they!are! ! implicated!in!synaptogenesis! 2nd!change:!2,454! and!the!modulation!of! homozygotes,!4,908! neurotransmitter!release,! allele!count,!allele! suggesting!a!potential!role!in! frequency:!1! several!neuropsychiatric! diseases.! , , , , , , , ! !

! 16! Supplementary,Table,2C:,Alternative,candidate,genes,identified,on,whole,exome,sequencing,–,Unverified,Changes,,

Gene, Gene,reference, DNA,change, Protein,change, Known,rs,No., PolyphenH2, SIFT, PROVEAN, Gene,function, Expression, Notes, NOTCH4% NM_004557! c.35_36insGCTGC p.L12delinsLLLL! NIL! NA! NA! NA! Encodes!a!member!of!the! Highest! Unable!to!design! TGCT! Notch!family..!Notch!family! expression!in! primers!for!Sanger! members!play!a!role!in!a! adipose!tissue,! sequencing!as!too!many! variety!of!developmental! expressed!in!brain! repetitions!in!gene!! processes!by!controlling!cell! sequence! fate!decisions.!! PRR21, NM_001080835! c.615_628del, p.H205fs, NIL, NA, NA, NA, May!be!involved!in!stress! Ubiquitously! Unable!to!design! ! responses!that!are!related!to! expressed,!as! primers!for!Sanger! ! phosphorylation!of! nearly! sequencing!as!too!many! ! mitochondrial!proteins.!!, all!eukaryotic!cells! repetitions!in!gene! ! contain! sequence, , mitochondria,

! 17! Supplementary,Figure,1:,TBC1D24%mutations,

Supplementary Figure 1: Identified TBC1D24 mutations and conservation data.

(A) Schematic diagram of the structure of TBC1D24 (B) The sequence chromatograms show in the top row the wild-type alleles (c.457G/G and c.545C/C of a control sample and in the row below the heterozygous alleles (c.457G/A and c.545C/- of an affected individual. (C) TBC1D24 amino acid sequences of 10 representative species are aligned. The affected amino acid (Glu153) is shown in red and bold. Residues matching the human protein sequence are in grey (dark grey when amino acid is conserved in all shown sequences) and those not matching the sequence are in white. [Nucleotide positions accordingly to NCBI reference sequences NM_001199107.1 and amino acid position accordingly to NCBI reference sequences NP_001186036.1]

! 18! Supplementary,Figure,2:,,EEG4EMG,, A

Supplementary,Figure,2:,EEG4EMG,,

(A) Patient!A1!age!3!years.!Multifocal!bursts!of!EMG!with!clinical!myoclonic!jerks.!Note!that!the!bursts!are!seen! independently!in!different!muscle!groups!on!the!right!and!left!side.!! (B) Patient! A2! aged! 12! months.! Apart! from! more! prominent! EMG! bursts! related! to! voluntary! movements! (left! deltoid,!left!biceps),!independent!brief!bursts!are!seen!recurrently!in!left!quadriceps,!and!in!isolation!in!other! muscles!independently.!! ! 19! !Supplementary,References:,

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