Genes and Development - Clinic for Special Childrengjc2 203a>g glb1 902c>t gldc 2186delc gldc 128dela hars 1361a>c hfe 187c>g hfe 845g>a hpd 85g>a hpd 479a>g hpd 1005c>g hsd3b2 35g>a
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Genes and Development
*No DisclosuresPhotos and Videos used with parental permission
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
Our Many Scientific and Clinical Collaborators
The Community we Serve
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