Diagnostic Odysseys

8/9/2019 Diagnostic Odysseys

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Dusica Babovic-Vuksanovic, MD

Professor of Genetics and Pediatrics

Chair, Department of Medical Genetics

Center for Individualized Medicine, Mayo Clinic

Diagnostic Odysseys


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• Mendelian disorders• Autosomal dominant• Autosomal recessive•

X-linked

…veysi!"#e$


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I

II

III

%utoso!a# do!inantin&eitance

Neurobromatosis

uberous sclerosis

Marfan s!ndrome

"hlers-Danloss!ndrome

#amilial cancers!ndromes

Achondoplasia


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%utoso!a# ecessivein&eitance

$%& $%& $%& $%&

Carrier

Normal

A'ected

Cystic brosisMetabolicdisordersSyndromes…


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'- n ein&eitance

Normal male

Normal female

A'ected male

Carrier female

Fragile X Duchenne muscular dystrohy !emohilia "


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(isk )o disease

55 y

Cleft

PalateMR

30 y 20 y 18 y

45 y

BRCA

48 y

MI

32 y

Dementia

DementiaColon Ca

80’s

MVA

15 y

CAD

70’sLn! Ca

75


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• Mitochondrial disorders

• Maternall! inherited

mDNA

Genetics o) &u!an disease

Is it so si!"#e*


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%NGE+M%N SND(OME (%DE( .I++I SND(OME

Maternaldeletion(paternal )PD

*ti' ata+ic ait

*evere M

Absent speechAlmost never obese

Paternaldeletion(maternal )PD

.!potonia

Developmental dela!

/besit!.!poonadism

/CD

E"igenetics !ec&anis!s


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• *everal enetic loci forthe

same phenot!pe

• Neurops!chiatricdisorders

• Autism

• *chi0ophrenia

• .earin loss• Non-s!ndromic• 1233 s!ndromes

&eteogeneity

Cell, Volume 141, Issue 2, 210-217, 16 April 2010

http://www.cell.com/issue?pii=S0092-8674(10)X0008-3http://www.cell.com/issue?pii=S0092-8674(10)X0008-3


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• #G#4• Achondroplasia• Crou0on s!ndrome(AN•

hanatophoricd!splasia

• 5AM6N A• Proeria• "D Musculard!stroph!

• Cardiom!opath!• 5ipod!stroph!

sa!e gene-di0eent

"&enoty"es


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• 6ncomplete penetrance Deletion(duplication $$7

• Ae dependent penetrance

Al0heimer disease

• Gender predisposition

X-linked disorders

.ip d!splasia

a a e"enetance


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%ntici"ation

Trinucleotide repeat disordersHuntington disease

Spinocerebellar ataxia

Myotonic Dystrophy

Fragile X syndrome


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Ne8 #rontiers

"nvironment, includinmicrobiome

6f the child looks like the father, it9s enetic the child looks like the neihbor, it9s environment


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• Non-Mendelian :common; disorders

• Multifactorial disorders• Genetics(environment comple+

interactions• Cleft lip(palate• Cancers• Diabetes• .!pertension• Ain


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Info"mation

#ontent of $man D%A

&A' (' )' o" C*

is + ,illion ,its in

e-e"y #ell' .it$ atotal len!t$ of

a,ot + feet of

D%A in e-e"y #ell

/ " o

m

N a

t u r e

' / e , 2

0 0

1


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• > $%,333 enes

• /ver 4,333 monoenic disorders

• .uman enome variations :Crai ?enter;

• 4,$@4,23@*NPs

• %4,$4 block substitutions :$B$3 bp;

• %%,2E4 homo0!ous indels :@B$,E@@ bp;

• $ CN?s

• $$,@3$ hetero0!ous insertion(deletion events:indels;:@B%E@ bp;

• 3 inversions

1u!an geno!e

5ev! et al=, #$oS %iol& $33E /ctoberF %:@3; e$%2


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• isk for disease• Predict response to

drus

• Pre-s!mptomaticdianosis forpreventable andtreatable disease

• ranslation to clinicalmedicine

• 6ncidental ndins

• "thical concerns• "motional distress• Cost of medical care

esona#i2ed !edicine/ Ea o)geno!ic se3uencing


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Gene screening may refine

prediction of heart attack risk,

researchers sayDec. 3, 2010 | This Week at Mayo Clinic | Volume 2, Number 1

Testing for 11 specific genetic variations in hunres of people

!ith no history of heart isease provie information that le torevision of their estimate heart attack risk, say Mayo Clinic

researchers "

Early findings suggest benefit may be most aluable in people thought tobe at intermediate risk using the current model

D" llo as' $o.e-e"' t$at t$ese finin!s nee to ,e "eli#ate an -aliate

in "ose#ti-e sties ,efo"e t$ey a"e se in atient #a"e


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.&at is a DiagnosticOdyssey*

• A protracted and arduous Hourne! forpatients and families to nd ans8ers abouta rare medical condition the! su'er from

• A lon se7uence of medical evaluationsand referrals until patients have aneventual dianosis

• are diseases a'ect about $% millionpeople in the )*

• Cumulativel!, rare diseases are not rare


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• $%& of patients on a dianostic od!sse!identied a ap of % to 43 !ears bet8een

ettin their rst s!mptoms and receivindianosis

• Iith advancements in enome se7uencin

more patients are ndin ans8ers to theirdianostic dilemmas

• *ome are even ndin lifesavintreatments

Diagnostic Odyssey in t&e

Ea o) ecision Medicine


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C!toenetic methods :kar!ot!pe, #6*. etc;

Chromosome anal!sis

Chromosome microarra!

areted microdeletion(duplication testin

Molecular methods :se7uencin, )PD, meth!lationassa! etc;

*inle ene anal!sis

Gene panels

"+ome anal!sis

Genome anal!sis

Genetic testing


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#rom Greor!, Nature evie8s Genetics , -E


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Geno!e se3uencing


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lgrdlmn!tthe!uick ababcmf"l!bro#nfo"$ulrcsmped

oerthela%yyy%polf dog $$irttiythedoglayhhbeld!uetly

dreamingh##i!ldnsofdinnerpl#osiucnd

lgrdlmn!tthe!uickababcmf"l!bro#nfo"$ulrcsmped

oerthela%yyy%polfdog$$irttiythedoglayhhbeld!uetly

dreamingh##i!ldnsofdinnerpl#osiucnd

4 bi##ionbases$


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25

o e 5o!e e3uenc ng


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Anal!sis of all e+ons@3,333 e+ons arraned in >$$,333 enesPortion of the human enome that contains protein-codin

se7uences$-4& of human enome

o e 5o!e e3uenc ng6.ES7


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• Genes related to clinical phenot!pe

• Medicall! actionable dianosis :ACMGG uidelines;

• Carrier status for A conditions :C#, a!-*achs, *ickle

Cell, #amilial D!sautonomia, Canavan disease, GPDdecienc!;

• Pharmacoenetic information :CJP$C andCJP$C@;, 8arfarin and Plavi+ metabolism

• Not included adult onset neurodeenerativedisorders

'tional e(ended reort includes deleteriousmutations and unclassied variants in genesunrelated to disease henotye and deleteriousmutations in genes )ith no currently *no)n function

.&o#e E5o!e Se3uencing6.ES7


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.&o#e e5o!e se3uencing

Ie9re not all the same

•Need to haveparental samples

• Comple+ test anddiKcult interpretation

• ?ariants ofunkno8nsinicance :?)*;

• 6ncidental ndins


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• 6M Clinic Iorkroup established in Lanuar!$3@$

• Multidisciplinar!, collaborative e'ort

• Desined(implemented t8o 6M Clinic servicelines

• *ept 43th, $3@$

• %dvanced Cance

• Diagnostic Odyssey

• -

Individua#i2ed Medicine 6IM7

C#inic


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• )ndianosed patients 8ith suspectedenetic component

• Ihole "+ome *e7uencin of "atient

enomic DNA and a0ected o un-a0ected e#atives - performed to ndenes contributin to disease

• D+ provides• Comfort, resolve, closure• 6nformation for famil! plannin• Possible therap!

IM C#inic/ Diagnostic Odyssey

Diagnostic Odyssey


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eConsulteferral into

6M Clinic

eferral toMa!o Clinic

• Genomic counseling

• IM Clinic Consultant meets patient

• Bioinormaticsanaly!es" generatesreport

• #esults presented to

Genomic Board• #esults and possible

treatment optionsreturned to patient

• $hole %xome Se&uencing

o germ'line

Diagnostic OdysseyIM C#inic

a s an a a


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a s an a aOde*


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evie8 ne8 cases and test results=Members include

IM C#inicGeno!ic Odyssey Boad 6GOB7

Diagnostic Odyssey


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.oloprosencephal!Central incisor

#acial cleftin

Diabetes insipidus

"ctrodact!l!

Developmental dela!

"CC :P4 ene;neative

Normal chromosome

arra!/d!sse! case

Diagnostic OdysseyCase 8


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1ats9e#d syndo!e


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Autosomal disorder

/nl! sporadic cases kno8n

ecurrence risk lo8O

1ats9e#d syndo!e


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"ctrodact!l!

.oloprosencephal!

Cleft lip and palate

.eart defect

Second c&i#d


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No other reported familial cases

I"* #G#@ ene novel variant c=@3G1C:p=$E;

$ a'ected siblins 8ith same mutation, parents

neativeecurrence riskO

1ats9e#d syndo!e


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"ctrodact!l!

.oloprosencephal!

Cleft palate

"ncephalocele

T&id c&i#d


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: a0ected sib#ings ;it& sa!e !utation, "aentsnegative, Odyssey continues$Tageted testing o) s"e!/


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• Ae $

• *e+ Male

• Proressive muscle 8eakness onset ae or E

•

DiKcult! sittin and standin up from sittinposition and diKcult! climbin stairs

• DiKcult! s8allo8in solid foods

• Mild form of ophthalmopleia

•

"levated C :24;

Diagnostic Odyssey Case


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Prior muscle biopsies not specic

No enetic testin :insurance problems;

eferred for I"*

evious Genetic Testing


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Personal histor!

Pediree anal!sis

Ph!sical e+amination

evie8 of previous evaluations

Di'erential dianosis

evie8 of literature

IM eva#uation


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(esu#ts

• Proressive m!opath!, suspicious famil! histor!,.utterite ancestr!

•

5imb-irdle muscular d!stroph! t!pe $. -Sarcotubular myoathy • Autosomal recessive disorder previousl! described

in .utterite population• areted ene testin


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IM C#inic > Diagnostic OdysseyConsecutive Cases o) 8? Mont&s in

O"eation

%## (e)ea#s

oceeded ;it&.ES@ testing

Dec#ined

.EStesting

Tota#

MedGen2$

$4 %

NonMedGen

@E

Tota# A :< ?<

IM C#inic Diagnostic Odyssey


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IM C#inic > Diagnostic OdysseyConsecutive Cases o) 8? Mont&s in O"eation

(eason )o (e)ea#

Neuo

Ae

Q%%-@

1@ otal

All referred @E $ E AAll tested 8ith I"* @3 @% :8

All positive @ % 4

Non-neuo

All referred $ $2 :<

All tested 8ith I"* @ 2 @2 8

All positive 3 @ 4

IM C#inic > Diagnostic Odyssey


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IM C#inic > Diagnostic OdysseyConsecutive Cases o) 8? Mont&s in

O"eation

Cases

otal Complete %3

Positive @%

Neative 4%

Success (ate :=


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IM C#inic > Diagnostic OdysseyConsecutive Cases o) 8? Mont&s in O"eation

(esu#ts > )o! C#inica# ocused e"ot

otal

ane perpatient

Averae

Pathoenic(likel! pathoenic

mutations

$$ 3-4

Medicall! actionableR $ 3-@

Carrier status 4 3-@

RRPGX E 3-2 $

RRR?)* possible related tophenot!pe

$$4 3-@ %=

( Medically actionable '' M)T*H +het," DSC- Carrier ' CFT#" G./D" F01CC

(( /GX2 /harmacogenomics

(((3ariants o un4no5n clinical signiicance


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Cost )o Eva#uating a atient ona

Diagnostic Odyssey

TestsSuccess

(ateCost

Conventional Genetic estinR

@%&>S$%,3

33

Ihole "+ome *e7uencin 43& S,333

Shashi 3 et al6" Genet Med 7.879.'-8-:7;

IM C#inic > Diagnostic Odyssey


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= Categoy

4@Patients received complete orpartial commercial insurancecoverae

$E Medicaid

@ C6M

6nternational patients

@ /ther

IM C#inic Diagnostic Odysseyaty (es"onsib#e )o ay!ent


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.ES and Sti## No Diagnosis/.&at is Ne5t

Vaiant Ty"e%ssociated

&enoty"e6s7epetitive DNA, includin

trinucleotide repeats#raile X s!ndrome

.untinton9s disease

Cop!-number variantsDiGeore s!ndrome

Charcot-Marie-ooth disease t!pe @A

5on insertion-deletion variantsR esistance to .6? infection

*tructural variantsChromosomal translocationsassociated 8ith spontaneous

abortions

Aneuploid!Do8n9s s!ndrome urner9s s!ndrome

"pienetic alterationsPrader-Iilli s!ndrome, Teck8ith-

Iiedemann s!ndrome

%ckno;#edge!e


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%ckno;#edge!ents

Center for 6ndividuali0ed Medicine5eadership

onstantinos N= 5a0aridis, M=D=

Department of Medical Genetics

David = De!le, M=D=

Pavel Pichurin, M=D=

alit0a Gavrilova, M=D=

Geo're! Teek, CGC

Lennifer emppainen, CGCMarine Murphree, CGC


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Fuestions


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e’"e not in t$e 6ost!enome e"a yet9

Diagnostic Odysseys

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