Genes and Development

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Kevin A. Strauss, MD*

Common Disorders, Uncommon Causes

ABCG8 1720G>AACADM 985A>GACADM IVS4-30A>GADA 646G>AADAMTS10 17,346 bp deletionAMN 44 bp deletionAPOA4 552_749dupATP8B1 923G>TBAAT 226A>GBBS1 1169T>GBCKDHA 1312T>ABTD 1459T>CBTD 1368A>CBTD 1330G>CC7orf10 895C>TC7orf27 638_639insACAPN3 2306G>ACFP 379T>GCHST3 1298C>TCLCNKB 22,508 bp deletionCNGA3 1126G>ACNTNAP2 3709delGCOL1A2 2098G>TCRADD 382G>CCYBB 1335C>ACYP11B1 1343G>ACYP11B2 5 bp deletion

DNAH5 4348C>TEDNRB 828G>TERCC6 IVS14+1G>TEVC IVS13+5G>TF11 1327C>TF5 1601G>AFLVCR1 361A>GFMR1 (CGG)n expansionGALT 563A>GGALT 940A>GGCDH 1262C>TGJB2 35delGGJC2 203A>GGLB1 902C>TGLDC 2186delCGLDC 128delAHARS 1361A>CHFE 187C>GHFE 845G>AHPD 85G>AHPD 479A>GHPD 1005C>GHSD3B2 35G>AIL7R 2T>GITCH 394_395insAKRIT1 47G>CLAMB2 440A>G

LMNA 568C>TLRP5 1225A>GLRP5 1275G>AMCCC2 295G>CMCCC2 518insTMCCC2 687A>CMKKS [250C>T + 724G>T]MTHFR 1129C>TMVK 803T>CMVK 1174G>ANPHS1 1481delCNPHS1 3250delGNPHS2 413G>ANTRK1 IVS12+1G>APAH 280_282delATCPAH 782G>APAH IVS10-11G>APAH IVS12+1GAPAH 782G>APCCB 1606A>GPEPD 793C>TPKLR 1436G>APYGL IVS13+1G>ARAG1 2974A>GRMRP 70A>GSERPINA1 1096G>ASGCB 452C>G

SGCB 271C>TSLC12A3 1924C>GSLC12A3 8,627 bp deletionSLC17A5 115C>TSLC25A19 530G>CSLC25A4 523delCSLC3A1 IVS6+2T>CSLC3A1 1354C>TSLC6A3 [1408T>A + 1409A>G]SLC6A3 IVS9+1G>TSLC7A9 201C>TSLC7A9 1166C>TSMN1 exon 7 deletionSPG20 1110delAST3GAL5 694C>TSTRADA 7 kb deletionTERT 1710C>GTH 698G>ATJP2 143T>CTMCO1 139_140delAGTNFRSF1A 362G>ATNNT1 505G>TTOR1A GAG deletionTSPYL1 457_458insGTUBGCP6 5458T>GUGT1A1 222C>AZMPSTE24 54_55insT

1000 Patients, 115 Disorders

Inborn&Error&of&Metabolism

Neurogene4c&Disability

Pallia4ve&Care

Mul4system&Dysplasia

CSC Core Expertise

Inborn&Error&of&Metabolism

Neurogene4c&Disability

Pallia4ve&Care

Mul4system&Dysplasia

CSC Core Expertise

Developmental Delay

61%

Language

Adaptive

Social

Motor

“To move things is all that mankind can do; For such the sole executant is muscle, whether in whispering a syllable or in felling a forest.”

Charles Sherrington, 1924

Motor

Language-Cognitive

Vision

Social-Emotional

Epilepsy

Hearing Loss

Behavior-Psychiatry

0 20 40 60 80 100

Developmental Delay (% Disorders)

Motor

Language-Cognitive

Vision

Social-Emotional

Epilepsy

Hearing Loss

Behavior-Psychiatry

0 20 40 60 80 100

Developmental Delay (% Disorders)

Motor

Adaptive Social

Language

Motor

Adaptive Social

Language

GCDHTHAP1TOR1ACHRNG

Motor

Adaptive Social

Language

FMR1CRADDANAPC7

Motor

Adaptive Social

Language

CNTNAP2STRADASNIP1

ST3GAL5

Upper Motor Neuron

Basal Ganglia

Cerebellum

Corticospinal

Lower Motor Neuron

Peripheral Nerve

16

PAHBCKDHABTD

SLC17A5LYK5FMR1PWSTH

AXPC1PCCBSMN1

AMN

Mennonite Child

PAHERCC6GCDH BBS1

CNTNAP2SPG20ACP33GJA12TSPYLGDAP1

BTDPCCB

MTHFRTNNT1SGCBCAPN3

Amish Child

Mennonite Child

16

PAHBCKDHA

BTDSLC17A5

LYK5FMR1PWSTH

AXPC1PCCB

SMN1

AMN

CODAS Syndrome

Motor

Adaptive Social

Language

Motor

Adaptive Social

Language

VisionHearing

Motor

Adaptive Social

Language

EpilepsyAutism

Motor

Adaptive Social

Language

DystoniaAtaxia

Neuropathy

Infantile SpasmsHemimegalencephaly

Complex Partial Symptomatic EpilepsySTRADA Deficiency

Autism Spectrum DisorderCNTNAP2 Deficiency

Complicated Cerebellar AtaxiaMTPAP Deficiency

28Brain Injury

Glutaric Aciduria 1

HealthyGlutaric Aciduria 1

“Idiopathic” Torsion DystoniaTHAP1 (DYT6)

Deep Brain Stimulation for Torsion Dystonia

“Idiopathic” Torsion DystoniaTOR1A (DYT1)

TreatmentDecisive

41%

TreatmentHelps38%

TreatmentIneffective

21%

Abnormal Nervous System Development

42%

Translational ScienceSTRADA 7kb Deletion

CollaborationTo Improve Patient Care

Cont

rol

STRA

DA

0 hrs 15 hrs

Cont

rol

STRA

DA

0 hrs 15 hrs

Siro

limus

Parker et al., Sci Transl Med 2013

New Treatment ParadigmsSirolimus Clinical Trial, N=6

New Diagnostic Paradigms

47

“We haven’t the money, so we’ve got to think.”

Lord Ernest Rutherford

MigrationBottleneck

Bottleneck

SwissAnabaptists

SwissMennoniteAmish

GroffdaleOther

Amish FOUNDERS

PAOHIN

Weaverland

MennoniteFOUNDERS

Identity-by-Descent2 Chromosomes in a Common Ancestor

Mutation

10-12 Generations

MutationRegion of

IBD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

TMCO1

Can the Methods Be

Generalized?

Developmental Delay and Next-Generation Technology

Novel (homozygous)Potentially Pathogenic Variants

New Patient

Presenting for Clinical Evaluation(N=150-250/year)

History & Physical ExamFamily History

Clinical Phenotype Tool (CPT)

RecognizableClinical Syndrome

ValidatedKnown Pathogenic Variants

Uninformative

1) Additional Family Studies2) Population Studies3) Functional Studies

Whole Genome

CytoScan Microarray

Novel ClinicalPhenotype

Targeted MutationDetection

Exome(s)single, trio, family

Novel (homozygous)Potentially Pathogenic Variants

New Patient

Presenting for Clinical Evaluation(N=150-250/year)

History & Physical ExamFamily History

Clinical Phenotype Tool (CPT)

RecognizableClinical Syndrome

ValidatedKnown Pathogenic Variants

Uninformative

1) Additional Family Studies2) Population Studies3) Functional Studies

Whole Genome

CytoScan Microarray

Novel ClinicalPhenotype

Targeted MutationDetection

Exome(s)single, trio, family

Novel (homozygous)Potentially Pathogenic Variants

New Patient

Presenting for Clinical Evaluation(N=150-250/year)

History & Physical ExamFamily History

Clinical Phenotype Tool (CPT)

RecognizableClinical Syndrome

ValidatedKnown Pathogenic Variants

Uninformative

1) Additional Family Studies2) Population Studies3) Functional Studies

Whole Genome

CytoScan Microarray

Novel ClinicalPhenotype

Targeted MutationDetection

Exome(s)single, trio, family

Novel (homozygous)Potentially Pathogenic Variants

New Patient

Presenting for Clinical Evaluation(N=150-250/year)

History & Physical ExamFamily History

Clinical Phenotype Tool (CPT)

RecognizableClinical Syndrome

ValidatedKnown Pathogenic Variants

Uninformative

1) Additional Family Studies2) Population Studies3) Functional Studies

Whole Genome

CytoScan Microarray

Novel ClinicalPhenotype

Targeted MutationDetection

Exome(s)single, trio, family

Mitochondrial Disorder?

Or . . . .

ZEB2 c.572_573insCCAAMowat-Wilson Syndrome

ZEB2 c.572_573insCCAAMowat-Wilson Syndrome

Thank You!D. Holmes MortonCaroline MortonErik G. PuffenbergerDonna RobinsonChristine Hendrickson Adam Heaps

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