LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
Conditions: Leukodystrophy, White Matter Disease, 4H Syndrome, Adrenoleukodystrophy, AMN, ALD, ALD (Adrenoleukodystrophy), X-linked Adrenoleukodystrophy, X-ALD, Adrenomyeloneuropathy, Aicardi Goutieres Syndrome, AGS, Alexander Disease, Alexanders Leukodystrophy, AxD, ADLD, Canavan Disease, CTX, Cerebrotendinous Xanthomatoses, Krabbe Disease, GALC Deficiency, Globoid Leukodystrophy, TUBB4A-Related Leukodystrophy, H-ABC - Hypomyelination, Atrophy of Basal Ganglia and Cerebellum, HBSL, HBSL - Hypomyelination, Brain Stem, Spinal Cord, Leg Spasticity, LBSL, Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and High Lactate Syndrome (Disorder), Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation, ALSP, CSF1R Gene Mutation, HCC - Hypomyelination and Congenital Cataract, MLC1, Megalencephalic Leukoencephalopathy With Subcortical Cysts 1, MLD, Metachromatic Leukodystrophy, PMD, Pelizaeus-Merzbacher Disease, PLP1 Null Syndrome, PLP1 Gene Duplication &#X7C; Blood or Tissue &#X7C; Mutations, Pelizaeus-Merzbacher-Like Disease, 1, Peroxisomal Biogenesis Disorder, Zellweger Syndrome, Refsum Disease, Salla Disease, Sialic Storage Disease, Sjögren, Sjogren-Larsson Syndrome, Van Der Knapp Disease, Vanishing White Matter Disease, Charcot-Marie-Tooth, CMT, Mct8 (Slc16A2)-Specific Thyroid Hormone Cell Transporter Deficiency, Allan-Herndon-Dudley Syndrome, Cadasil, Cockayne Syndrome, Multiple Sulfatase Deficiency, Gangliosidoses, GM2 Gangliosidosis, BPAN, Labrune Syndrome, LCC, Mucopolysaccharidoses, TBCK-Related Intellectual Disability Syndrome
Sponsor: Children's Hospital of Philadelphia

 
  1  
 
F ull Title:  
Le u k o S E Q: W h ole Ge n o me Se q ue nci n g as a First -Li ne 
Di a g n ostic T o ol f or Le u k o d ystr o p hies  
S h ort Title  
Le u k o S E Q  
eI R B N o.:  
1 6 -1 3 2 1 3  
Pr ot oc ol D ate:  
9/ 1 2 / 2 0 1 6 
A me n d me nt 3  D ate:  A pril 2 0 1 8 ( F ull 
A m d.)  
A me n d me nt 4  D ate:  Dece m ber 2 0 1 8 ( F ull 
A m d.)  
A me n d me nt 6  D ate:  Ma y 2 0 1 9 ( F ull A m d.)  A me n d me nt 1 7  D ate:  Se pte m ber 2 0 2 4 
( F ull A m d.) 
Ple ase n ote t h at t he a b o ve list d oes n ot i ncl u de ‘ St aff C h a n ge’ a me n d me nts.  
 St u d y Pri nci p al I n vesti g at or  
A deli ne Va n der ver, M D  
T he C hil dre n’s H os pital of P hila del p hia  
3 6 1 5 Ci vic Ce nter Bl v d. A R C 5 1 6 H  
P hila del p hia, P A 1 9 1 0 4  
e mail: va n der vera @c h o p.e d u  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  2  
T A B L E O F C O N T E N T S  
 
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ......................................................................................... 4  
A B S T R A C T  ...................................................................................................................................................................... 5  
1  
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E  ............................................................................ 5  
1. 1  
IN T R O D U C TI O N  ................................................................................................................................................................. 5  
1. 2  
R A TI O N A L E F O R A P P R O A C H  ........................................................................................................................................ 7  
1. 3  
C O M P LI A N C E S T A T E M E N T  ............................................................................................................................................ 7  
2  
S T U D Y O B J E C TI V E S  ........................................................................................................................................ 7  
2. 1  
P RI M A R Y O BJ E C TI V E (O R A I M 1)  ............................................................................................................................... 7  
2. 2  
S E C O N D A R Y O BJ E C TI V E (O R A I M 2)  ......................................................................................................................... 8  
3  
I N V E S TI G A TI O N A L P L A N ............................................................................................................................. 8  
3. 1  
G E N E R A L S C H E M A O F S T U D Y D E SI G N  ..................................................................................................................... 8  
 
Scr e e ni n g Pr oc e d ur es  ................................................................................................................................................. 8  
 
F oll o w -U p P eri o d ( 1 2 M o nt hs F O L L O WI N G R E P O R T)  ................................................................................. 8  
 
E arl y T er mi n ati o n a n d Wit h dr a w al  ..................................................................................................................... 9  
3. 2  
S T U D Y D U R A TI O N , E N R O L L M E N T A N D N U M B E R O F S I T E S ................................................................................ 9  
 
D ur ati o n of St u d y P artici p ati o n  ............................................................................................................................. 9  
 
T ot al N u m b er of St u d y Sit es / T ot al N u m b er of S u bj ects Pr oj ect e d  ........................................................ 9  
3. 3  
P R O S P E C TI V E S T U D Y P O P U L A TI O N ( W G S C O H O R T ) ........................................................................................... 9  
 
I ncl usi o n Crit eri a & I niti al C a n di d at e Ass ess me nt ......................................................................................... 9  
 
I ncl usi o n Crit eri a –  All C a n di d at es  ....................................................................................................................... 9  
 
Excl usi o n Crit eri a –  All C a n di d at es  ....................................................................................................................... 9  
 
I ncl usi o n Crit eri a - P ar e nts  ................................................................................................................................... 1 0  
 
Excl usi o n Crit eri a - P ar e nts  .................................................................................................................................. 1 0  
4  
S T U D Y E V A L U A TI O N S A N D M E A S U R E M E N T S  ................................................................................ 1 0  
4. 1  
S T U D Y O U T C O M E M E A S U R E S  .................................................................................................................................. 1 0  
 
Pr os p ecti v e C oll ecti o n of Cli nic al Utilit y D at a  .............................................................................................. 1 0  
 
O utc o me Me as ur e D efi niti o ns  .............................................................................................................................. 1 1  
4. 2  
S A F E T Y E V A L U A TI O N  ................................................................................................................................................. 1 1  
5  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................................................... 1 1  
5. 1  
A N A L Y SI S P L A N A N D S A M P L E S I Z E D E T E R MI N A TI O N  ...................................................................................... 1 1  
 
A n al ysis f or Ai m 1  ...................................................................................................................................................... 1 1  
 
A n al ysis f or Ai m 2  ...................................................................................................................................................... 1 1  
 
S a m pl e Siz e D et er mi n ati o n  ................................................................................................................................... 1 2  
 
Missi n g D at a  ................................................................................................................................................................ 1 2  
 ................. T H E P R O P O R TI O N O F S U BJ E C T S W H O W E R E L O S T T O F O L L O W -U P WI L L B E R E P O R T E D. 
 .......................................................................................................................................................................................... 1 2  
6  
S A F E T Y M A N A G E M E N T  ............................................................................................................................. 1 2  
7  
S T U D Y M A N A G E M E N T  ................................................................................................................................ 1 2  
7. 1  
D A T A C O L L E C TI O N A N D M A N A G E M E N T  .............................................................................................................. 1 2  
7. 2  
C O N FI D E N TI A LI T Y  ........................................................................................................................................................ 1 2  
7. 3  
R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S  ................................................................................................. 1 3  
 
Ris k Ass ess me nt, G e n er al C o nsi d er ati o ns  ....................................................................................................... 1 3  
 
Ps yc h ol o gic al H ar ms  ................................................................................................................................................ 1 3  
 
Discri mi n ati o n  ............................................................................................................................................................ 1 3  

 
  3  
 
C o nfi d e nti alit y of Me dic al I nf or m ati o n a n d S a m pl es  ................................................................................ 1 3  
 
P ot e nti al B e n efits  ...................................................................................................................................................... 1 3  
 
Ris k -B e n efit Ass ess me nt  ......................................................................................................................................... 1 3  
7. 4  
R E C R UI T M E N T S T R A T E G Y  ......................................................................................................................................... 1 3  
7. 5  
IN F O R M E D C O N S E N T / AS S E N T A N D HI P A A  A U T H O RI Z A TI O N  ....................................................................... 1 4  
 
S h ort F or m C o ns e nt Pr oc ess R e q uiri n g T el e p h o nic I nt er pr et ati o n S er vic es  .................................. 1 5  
 
HI P A A Att est ati o n f or t h e Us e of D ec e d e nt P HI  ........................................................................................... 1 5  
7. 6  
P A Y M E N T T O S U BJ E C T S / FA MI LI E S  .......................................................................................................................... 1 5  
8  
P U B LI C A TI O N  ................................................................................................................................................. 1 6  
9  
R E F E R E N C E S  ................................................................................................................................................... 1 7  

 
  4  
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
 
A D E M  
 
A c ute D isse mi nate d E nce p hal o m yelitis  
C LI A  
 
Cli nical La b orat or y I m pr o ve me nt A me n d me nts  
D U A  
 
Data Use A gree me nt  
HI P A A  
 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
I C S L 
 
Ill u mi na Cli nical Ser vices La b orat or y 
I R B 
 
I nstit uti o nal Re vie w B oar d 
M D B P  
 
M yeli n Dis or ders Bi ore p osit or y Pr oject  
M RI  
 
Ma g netic Res o na nce I ma gi n g  
N G S  
 
Ne xt Ge nerati o n Se q ue nci n g  
P HI  
 
P r otecte d Healt h I nf or mati o n  
PI  
 
Pri nci pal I n vesti gat or  
S A E  
 
Seri o us A d verse E ve nt  
S o C  
 
Sta n dar d of Care  
V U S  
 
Varia nt of U n k n o w n Si g nifica nce  
W E S  
 
W h ole E x o me Se q ue nci n g  
W G S  
 
W h ole Ge n o me Se q ue nci n g  
 
 
 

 
  5  
A B S T R A C T  
C o nte xt /B ac k gr o u n d : 
Le u k o d ystr o p hies, a n d ot her herita ble dis or ders of t he w hite matter of t he brai n, were 
pre vi o usl y resista nt t o ge netic c haracterizati o n, lar gel y d ue t o t he e xtr e me ge netic 
heter o ge neit y of m olec ular ca uses. W hile rece nt w or k has de m o nstrate d t hat w h ole ge n o me 
se q ue nci n g ( W G S) has t he p ote ntial t o dra maticall y i ncrease dia g n ostic efficie nc y, 
si g nifica nt q uesti o ns re mai n ar o u n d t he i m pact o n d o w nstrea m cli nical ma na ge me nt 
a p pr oac hes vers us sta n dar d dia g n ostic a p pr oac hes.  
O bjecti ves: ( Pri m ar y a n d I m p ort a nt Sec o n d ar y O bjecti ves)  
Pri m ar y  
 
•  
Esti mate t he perce nta ge of cases t hat e x perie nce a si g nifica nt c ha n ge i n dia g n ostic stat us  
as a direct c o nse q ue nce of w h ole ge n o me se q ue nci n g.  
Sec o n d ar y  
 
•  
Esti mate t he perce nta ge of cases t hat e x perie nce a si g nifica nt c ha n ge i n d o w nstrea m 
cli nical ma na ge me nt as a direct c o nse q ue nce of a dia g n o stic res ult t hr o u g h w h ole 
ge n o me se q ue nci n g . 
St u d y Desi g n:  
O bser vati o nal st u d y pre dicate d o n p ositi ve fi n di n gs of a ra n d o mize d cr oss o ver st u d y, w hic h 
de m o nstrate d s u peri or dia g n ostic efficac y of W G S c o m pare d t o sta n dar d dia g n ostic testi n g. 
Setti n g/ P artici p a nts:  
T his is a si n gle -site st u d y l ocate d at t he C hil dre n’s H os pital of P hila del p hia ( C H O P). St u d y 
recr uit me nt will c o nti n ue u ntil 1 0 0 tri os ( or d u os) ha ve bee n e nr olle d.  
St u d y I nter ve nti o ns a n d Me as ures:  
T his is a n o bser vati o nal st u d y of s u bjects w h o are e x pecte d t o recei ve C LI A -certifie d w h ole 
ge n o me se q ue nci n g as part of t heir cli nical care . Researc h-o nl y meas ures will i ncl u de b ot h 
retr os pecti ve a n d pr os pecti ve re vie w of me dical rec or ds. 
M ai n St u d y O utc o me Me as ures:  
Cli nical utilit y o utc o mes will be assesse d usi n g me dical rec or d re vie w.  
1  
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E  
1. 1  
I ntr o d ucti o n 
Le u k o d ystr o p hies are a gr o u p of a p pr o xi matel y 3 0 ge netic diseases t hat pri maril y affect t he 
w hite matter of t he brai n 1, 2, a c o m ple x str uct ure c o m p ose d of a x o ns s heat he d i n m yeli n, a 
glial cell -deri ve d li pi d -ric h me m bra ne1. Le u k o d ystr o p hies are fre q ue ntl y c haracterize d b y 
earl y o nset, s pasticit y a n d de vel o p me ntal dela y, a n d are de ge nerati ve i n nat ure 1. As a w h ole, 

 
  6  
le u k o d ystr o p hies are relati vel y c o m m o n (a p pr o xi matel y 1 i n 7 0 0 0 birt hs or al m ost t wice as 
pre vale nt as Pra der -Willi S y n dr o me, w hic h has bee n far m ore e xte nsi vel y st u die d) wit h hi g h 
ass ociate d healt h -care c osts; h o we ver, m ore t ha n half of t he s us pecte d le u k o d ystr o p hies d o 
n ot ha ve a  defi niti ve dia g n osis 3, 4, a n d are ge nerall y classifie d as “le u k o d ystr o p hies of 
u n k n o w n eti ol o g y”. E ve n w he n a dia g n osis is ac hie ve d, t he dia g n ostic pr ocess lasts a n 
a vera ge of ei g ht years 5 a n d res ults i n test e x pe nses i n e xcess of $ 8, 0 0 0 o n a vera ge per 
patie nt, i ncl u di n g t he maj orit y of patie nts w h o ne ver ac hie ve a dia g n osis at all 6, 7. T hese 
dia g n ostic c halle n ges re prese nt a n ur ge nt a n d u nres ol ve d ga p i n k n o wle d ge a n d disease 
c haracterizati o n, as o btai ni n g a defi niti ve dia g n osis is of para m o u nt i m p orta nce f or 
le u k o d ystr o p h y patie nts8. T he dia g n ostic w or k u p be gi ns wit h fi n di n gs on cra nial Ma g netic 
Res o na nce I ma gi n g ( M RI) f oll o we d b y se q ue ntial tar gete d ge netic testi n g 1, h o we ver ne xt 
ge nerati o n se q ue nci n g ( N G S) tec h n ol o gies offer t he pr o mise of ra pi d a n d m ore c ost 
effecti ve a p pr oa c hes. 
 N G S tec h n ol o gies ha ve t he p ote ntial t o re v ol uti o nize t he dia g n ostic pr ocess f or rare 
diseases, es peciall y t h ose s uc h as t he le u k o d ystr o p hies, w hic h ha ve see n s uc h hist oricall y 
l o w rates of dia g n osis. O ur i nter nati o nal w or ki n g gr o u p (s pear hea de d b y Drs. Van der ver, 
Taft, B o n k o ws k y, Ber nar d, Sc hiff ma n n, a n d va n der K naa p) has e xte nsi ve a n d gl o ball y 
rec o g nize d e x pertise i n deci p heri n g t he ge netics u n derl yi n g u ns ol ve d le u k o d ystr o p hies. 
T he y c ollecti vel y ha ve bee n t he lar gest c o ntri b ut or t o t he m o der n u n dersta n d i n g of 
le u k o d ystr o p h y eti ol o g y a n d pat h o bi ol o g y. T his b o d y of w or k o ver t he last deca des i ncl u des 
t he descri pti o n of Va nis hi n g W hite Matter Disease (EI F 2 B 1 -5 )1 8 -2 0, 4 H s y n dr o me ( P O L 3 R A 
a n d B )2 1 -2 3, Le u k oe nce p hal o pat h y wit h Brai nste m a n d S pi nal C or d I n v ol ve me nt a n d Lactate 
Ele vati o n ( D A R S 2 )2 4, 2 5, Me gale nce p halic Le u k oe nce p hal o pat h y wit h s u bc ortical C y sts 
(M L C 1 a n d H E P A C A M )2 6, 2 7, Le u k oe nce p hal o pat h y wit h T hala mic i n v ol ve me nt a n d Lactate 
a n d Sl o w I m pr o ve me nt ( E A R S 2 )2 8, 2 9. 
I n t he last se veral years, t he pace of disc o ver y has i ncrease d at a re mar ka ble rate d ue t o t he 
use of w h ole ge n o me se q ue nci n g ( W G S) a n d w h ole e x o me se q ue nci n g ( W E S). T his 
i ncl u des t he disc o ver y of a n o vel le u k o d ystr o p h y, H y p o m yeli nati o n wit h Brai n Ste m a n d 
S pi nal C or d I n v ol ve me nt a n d Le g S pasticit y ( H B S L) , w hic h is ca use d b y m utati o ns i n 
D A R S 3 0, as well as t he disc o ver y t hat H y p o m yeli nati o n wit h Atr o p h y of t he Basal Ga n glia 
a n d Cere bell u m ( H -A B C) is ca use d b y de n ov o  T U B B 4 A  m utati o ns 3 1. Fi nall y, o ur gr o u p has 
perf or me d t he first c o h ort a nal ysis of W E S i n le u k o d ystr o p h y, wit h a dia g n ostic efficac y i n 
t he u ns ol ve d patie nts of nearl y 5 0 %, decreasi n g t he o verall pr o p orti o n of u ns ol ve d 
le u k o d ystr o p h y cases fr o m 5 0 % t o a p pr o xi matel y 2 5 %. 
Des pite t hese a d va nces i n dia g n ostic efficac y, t here are still si g nifica nt iss ues wit h res pect t o 
i m ple me ntati o n of N G S i n cli nical setti n gs. First, sa m ple c o h orts de m o nstrati n g dia g n ostic 
efficac y are ge nerall y s mall, retr os pecti ve, a n d s usce pti ble t o asc ertai n me nt bias, ulti matel y 
re n deri n g t he m p o or ca n di dates f or utilit y a nal yses (t o deter mi ne h o w efficie nt a test is at 
pr o d uci n g a dia g n osis). Sec o n d, hist oric sa m ple c o h orts ha ve n ot bee n e xa mi ne d 
pr os pecti vel y f or i nf or mati o n a b o ut i m pact o n cli nical m a na ge me nt ( w het her t he test res ults 
i n differe nt cli nical m o nit ori n g, a c ha n ge i n me dicati o ns, or alter nate cli nical i nter ve nti o ns).  
T o a d dress t hese iss ues, t he st u d y tea m c o n d ucte d a n i n vesti gati o n of patie nts wit h 
s us pecte d le u k o d ystr o p hies or ot her ge netic dis or ders affecti n g t he w hite matter of t he brai n 
at t he ti me of i nitial c o nfir mati o n of M RI a b n or malities, wit h pr os pecti ve c ollecti o n of 
patie nts ra n d o ml y recei ve d o n a “first c o me, first ser ve d” basis fr o m a net w or k of e x pert 

 
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cli nical sites. S u bjects were ra n d o mize d t o recei ve earl y ( 1 m o nt h) or late ( 6 m o nt hs) W G S, 
wit h  Sta n dar d of Care  (S o C ) cli nical a nal yses c o n d ucte d al o n gsi de W G S testi n g. A n i nteri m 
a nal ysis perf or me d i n Ma y 2 0 1 8 assesse d t hese st u d y o utc o mes f or a c o h ort of t hirt y -f o ur 
( 3 4) e nr olle d s u bjects. T w o of t hese s u bjects were res ol ve d bef ore c o m plete e nr oll me nt a n d 
were retai ne d as c o ntr ols. Ni ne s u bjects were stratifie d t o t he I m me diate Ar m, of w hic h 5 
( 5 5. 6 %) were res ol ve d b y W G S a n d 4 ( 4 4. 4 %) were persiste ntl y u nres ol ve d. Of t he 2 3 
s u bjects ra n d o mize d t o t he Dela ye d Ar m, 1 4 ( 6 0. 9 %) were res ol ve d b y W G S a n d 5 ( 2 1. 7 %) 
b y S o C, w hile t he re mai ni n g 4 ( 1 7. 4 %) re mai ne d u n dia g n ose d. T he dia g n ostic efficac y of 
W G S i n b ot h ar ms was si g nifica nt relati ve t o S o C ( p < 0. 0 0 5). T he ti me t o dia g n osis was 
si g nifica ntl y s h orter i n t he i m me diate W G S gr o u p ( p < 0. 0 5). T he o verall dia g n ostic efficac y 
of t he c o m bi nati o n of W G S a n d S o C a p pr oac hes was 2 6/ 3 4 ( 7 6. 5 %; 9 5 % CI = 5 8. 8 % t o 
8 9. 3 %) o ver < 4 m o nt hs, greater t ha n hist orical n or ms of < 5 0 % o ver m ore t ha n 5 years.  
1. 2  
R ati o n ale f or A p pr o ac h  
We a ntici pate t hat w h ole ge n o me se q ue nci n g will pr o d uce meas ura ble d o w nstrea m  c ha n ges 
i n dia g n ostic stat us a n d  cli nical ma na ge me nt, as defi ne d b y disease -s pecific scree ni n g f or 
c o m plicati o ns or i m ple me ntati o n of disease -s pecific t hera pe utic a p pr oac hes.  
1. 3  
C o m pli a nce St ate me nt  
T his st u d y will be c o n d ucte d i n f ull acc or da nce wit h  all a p plica ble C hil dre n’s H os pital of 
P hila del p hia Researc h  ( C H O P) P olicies a n d Pr oce d ures a n d all a p plica ble Fe deral a n d state 
la ws a n d re g ulati o ns, i ncl u di n g 4 5 C F R 4 6, a n d t he HI P A A Pri vac y R ule. A n y e pis o de of 
n o nc o m plia nce will be d oc u me nte d.  
T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will o btai n 
c o nse nt a n d asse nt, a n d will re p ort u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o researc h 
s u bjects or ot hers. C ollecti o n, rec or di n g, a n d re p orti n g of data will be acc urate a n d will 
e ns ure t he pri vac y, healt h, a n d welfare of researc h s u bjects d uri n g a n d after t he st u d y.  
2  
S T U D Y O B J E C TI V E S  
T his st u d y see ks t o deter mi ne w het her W G S res ults i n c ha n ges t o dia g n ostic stat us a n d 
cli nical ma na ge me nt i n s u bjects affecte d b y u n dia g n ose d ge netic dis or ders of t he w hite 
matter of t he brai n.  
2. 1  
Pri m ar y O bjecti ve ( or Ai m  1 ) 
Esti m ate t he perce nt a ge of c ases t h at e x perie nce a si g nific a nt c h a n ge i n di a g n ostic 
st at us  as a direct c o nse q ue nce of w h ole ge n o me se q ue nci n g.  
 
T he pri mar y o bjecti ve of t his st u d y is t o e val uate c ha n ges i n dia g n ostic stat us i n t he st u d y 
c o h ort f or patie nts w h o recei ve d W G S as part of cli nical care. Differe nces i n dia g n ostic 
stat us will be meas ure d at  discl os ure of i nitial res ults or discl os ure of rea nal yze d res ults.   
 
T y pes of c ha n ge i n ma na ge me nt are defi ne d i n Secti o n 5. 1. 4.  
 

 
  8  
2. 2  
Sec o n d ar y O bjecti ve ( or Ai m  2 ) 
Esti m ate t he perce nt a ge of c ases t h at e x perie nce a si g nific a nt c h a n ge i n d o w nstre a m 
cli nic al m a n a ge me nt as a direct c o nse q ue nce of a di a g n osis t hr o u g h w h ole ge n o me 
se q ue nci n g (s u bjects wit h a di a g n ostic res ult). 
T he sec o n dar y o bjecti ve of t his st u d y is t o e val uate c ha n ges i n cli nical care i n s u bjects w h o 
recei ve d a dia g n osis t hr o u g h W G S. Differe nces i n cli nical care will be e val uate d 1 year 
f oll o wi n g discl os ure of res ults.  
 
3  
I N V E S TI G A TI O N A L P L A N 
3. 1  
Ge ner al Sc he m a of St u d y Desi g n  
T his is a n o bser vati o nal st u d y of s u bjects w h o are e x pecte d t o recei ve C LI A -certifie d w h ole 
g e n o me se q ue nci n g as part of t heir cli nical care.  
 Scree ni n g Pr oce d ure s 
Ca n di dates wit h a s us pecte d le u k o d ystr o p h y or ot her s us pecte d ge netic dis or der affecti n g 
t he w hite matter of t he brai n will be pr o vi de d wit h i nf or mati o n a b o ut t he st u d y b y a 
q ualifie d me m ber of t he st u d y tea m. I ntereste d ca n di dates will be i n vite d t o e nr oll i n C H O P 
I R B 1 4-0 1 1 2 3 6 t o facilitate c ollecti o n a n d re vie w of me dical rec or ds. At a mi ni m u m, t hese 
rec or ds m ust i ncl u de a c o p y of t he m ost rece nt ne ur ol o gic e xa m a n d brai n M RI. A d diti o nal 
n otes, re p orts, test res ults, i ma gi n g st u dies, etc. will be re q uest e d if a vaila ble.  
Ca n di dates  w h o meet basic eli gi bilit y re q uire me nts  will t he n be i n de pe n de ntl y re vie we d b y 
Dr. Ge ne vie ve Ber nar d , M D, a pe diatric ne ur ol o gist at Mc Gill U ni versit y wit h si g nifica nt 
e x pertise i n M RI patter n rec o g niti o n . Dr. Ber nar d ma y recei ve a bstract cli nical s u m maries, 
as well as ra di ol o g y st u dies t hat ha ve bee n c o de d wit h a u ni q ue st u d y i de ntifier ge nerate d b y 
t he C H O P st u d y tea m. Dr. Ber nar d will n ot be a ble t o li n k t hese st u d y i de ntifiers t o P HI. 
M RIs will be a nal yze d acc or di n g t o a p u blicl y  a vaila ble n o n -c o m p utati o nal al g orit h m 
accessi ble t o e ve n n o n -e x pert c hil d ne ur ol o gists a n d ge neticists 4 6. Ca n di dates  ma y be 
e nr olle d irres pecti ve of t he cli nicia n’s pres u m pti ve dia g n osis (e ve n if t he cli nicia n feels 
t here is a n u na m bi g u o us dia g n osis base d o n M RI a n d i nitial cli nical assess me nt), as l o n g as 
n o c o nfir mat or y testi n g has bee n perf or me d . Eac h ca n di date’s M RIs m ust be re vie we d b y at 
least t w o of t he f o ur e x perts. If necessar y, ca n di dates  will be reclassifie d wit h res pect t o 
t heir pre-test dia g n ostic pr o ba bilities. 
 F oll o w -U p Peri o d ( 12  M o nt hs  F O L L O WI N G R E P O R T ) 
S u bjects e nr olle d i n t he st u d y will c o nc urre ntl y u n der g o W G S as part of t heir cli nical care, 
wit h sa m ples se nt t o t he Ill u mi na Cli nical Ser vices La b orat or y (I C S L) f or cli nicall y -
vali date d testi n g.  
 

 
  9  
 E arl y Ter mi n ati o n a n d W it h dr a w al 
S u bjects ma y wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n. T his w o ul d res ult i n 
re m o val of a n y i de ntif yi n g i nf or mati o n fr o m rec or de d data bases. 
3. 2  
St u d y D ur ati o n, E nr oll me nt a n d N u m ber of Sites  
 D ur ati o n of St u d y P artici p ati o n  
St u d y partici pati o n will last f or 1 2 m o nt hs f oll o wi n g t he discl os ure of res ults.   
 T ot al N u m ber of St u d y Sites/ T ot al N u m ber of S u bjects Pr ojecte d  
T his is a si n gle -site st u d y l ocate d at t he C hil dre n’s H os pital of P hila del p hia ( C H O P).  St u d y 
recr uit me nt will c o nti n ue u ntil 1 0 0  tri os ( or d u os) ha ve bee n e nr olle d.  
3. 3  
Pr os pecti ve St u d y P o p ul ati o n ( W G S C o h ort)  
 I ncl usi o n Criteri a & I niti al C a n di d ate  Assess me nt  
T hese criteria ha ve bee n selecte d i n or der t o e ns ure t hat selecte d cases fit t he defi niti o n of a 
le u k o d ystr o p h y 3 3 a n d all o w acc urate calc ulati o ns of dia g n ostic efficac y base d o n ti me t o 
dia g n osis fr o m i nitial i de ntificati o n of a w hite matter dis or der.  T he herita ble le u k o d ystr o p hies 
affect males a n d fe males e q uall y, wit h t he e xce pti o n of Pelizae us Merz bac her a n d A L D, 
w hic h are X -li n ke d. We e x pect t heref ore t hat males a n d fe males will be e q uall y re prese nte d i n 
t he p o p ulati o n of patie nts wit h u nclassifie d le u k o d ystr o p hies. T he a ge of prese ntati o n is 
varia ble , ra n gi n g fr o m i nfa nc y t o a d ult h o o d. All et h nicities are e q uall y re prese nte d i n t hese 
dis or ders, a n d we e x pect et h nicities t o be re prese nte d  base d o n U .S . ce ns us data of p o p ulati o n 
distri b uti o n.  
 I ncl usi o n Criteri a –  All C a n di d ates  
1)  A b n or malities of t he w hite matter si g nal o n ne ur oi ma gi n g ( M RI) wit h T 2 
h y peri nte nsit y w hic h m ust be diff use or i n v ol ve s pecific a nat o mical tracts 
c o nsiste nt wit h a ge netic dia g n osis ;  
2)  N o pre -e xisti n g ge netic dia g n osis;  
3)  A cli nical decisi o n has bee n ma de t o perf or m W G S ; 
4)  Less t ha n 1 8 years of a ge  (e xce pti o n f or affecte d si bli n g of t he pr o ba n d);  
5)  A vaila bilit y of b ot h bi ol o gic pare nts f or bl o o d sa m pli n g ; 
6)  A vaila bilit y of b ot h bi ol o gical pare nts  t o pr o vi de i nf or me d c o nse nt; 
7)  C o nc urre ntl y e nr olle d i n C H O P I R B 1 4 -0 1 1 2 3 6 ( M yeli n Dis or ders 
Bi ore p osit or y Pr oject ) 
 
 E xcl usi o n Criteri a  –  All C a n di d ates  
1)  Ca n di dates wit h ac q uire d dis or ders, i ncl u di n g i nfecti o n, ac ute disse mi nate d 
e nce p hal o m yelitis ( A D E M), m ulti ple scler osis, vasc ulitis or t o xic 
le u k oe nce p hal o pat hies; 
2)  Patie nts w h o ha ve ha d pre vi o us ne xt -ge nerati o n ge netic se q ue nci n g* , 
i ncl u di n g W E S or  W G S ; 
3)  T h ose wit h n o t hir d -part y pa yer i ns ura nce, u na ble t o recei ve sta n dar d of care 
dia g n osis a n d t hera pe utic a p pr oac hes ; 

 
  1 0  
4)  Ca n di dates w h o ha ve alrea d y recei ve d a dia g n osis . 
 
* N ote:  K ar y ot y pe or  micr oarra y testi n g t hat di d n ot yiel d a defi niti ve dia g n osis s h o ul d n ot 
be c o nsi dere d as a n e xcl u di n g fact or.  
 
 I ncl usi o n Criteri a - P are nts  
1)  Males or fe males 1 8 years or ol der ; 
2)  C hil d wit h a s us pecte d le u k o d ystr o p h y  or ot her s us pecte d ge netic dis or der 
affecti n g t he w hite matter of t he brai n.  
 
 E xcl usi o n Criteri a  - P are nts  
1)  I na bilit y t o pr o vi de c o nse nt; 
2)  Pre g na nt w o me n a n d fet uses will n ot be i ncl u de d i n t his st u d y . 
 
Ca n di dates w h o d o n ot meet all of  t he e nr oll me nt criteria ma y n ot be e nr olle d. Vi olati o ns  of 
t hese criteria will be re p orte d i n acc or da nce wit h I R B P olicies a n d Pr oce d ures.  
4  
S T U D Y E V A L U A TI O N S A N D M E A S U R E M E N T S  
4. 1  
St u d y O utc o me Me as ures  
 Pr os pecti ve C ollecti o n of Cli nic al Utilit y D at a  
Cli nical  utilit y o utc o mes will be assesse d usi n g a c o m bi nati o n of me dical rec or d re vie w  1 
year pri or t o (retr os pecti ve) a n d 1 year f oll o wi n g  ( pr os pecti ve) discl os ure of res ults.  A n 
a p pr o priatel y trai ne d me m ber of t he st u d y tea m will re vie w t his data f or d oc u me nte d  
c ha n ges i n care a n d cli nical state, i ncl u de d c ha n ges i n me dical m or bi dities, s ur geries, 
p har mac ol o gic ma na ge me nt of c o m plicati o ns a n d i m ple me ntati o n of disease s pecific 
t hera pies. T he f oll o wi n g data ele me nts will be a bstracte d fr o m patie nt me dical rec or ds f or 
a nal ysis. 
•  D ia g n ostic stat us ( pri mar y): Res ults were dia g n ostic, n o n -dia g n ostic ( ne gati ve or 
varia nt of u n k n o w n si g nifica nce ( V U S ) wit h i nc o nsiste nt p he n ot y pe ), u ncertai n 
(pre vi o usl y a n d/ or n ot pre vi o usl y re p orte d V U S  i de ntifie d a n d re q uires f oll o w-u p ). 
•  I m plicati o ns of W G S: c o nfir me d a dia g n osis wit hi n t he differe ntial dia g n osis pri or t o 
testi n g, esta blis he d a ne w dia g n osis t hat was n ot pre vi o usl y s us pecte d, pr o d uce d a 
dia g n osis u nrelate d t o t he cli nical i n dicati o n f or testi n g [i ncl u des i nci de ntal fi n di n g s 
a n d/ or sec o n dar y fi n di n gs], r ule d o ut a s us pecte d dia g n osis/ dia g n oses, eli mi nate d 
t he nee d f or a d diti o nal tests or e val uati o ns, c o ntri b ute d t o t he o verall dia g n ostic 
e val uati o n of t his patie nt.  
o  Dia g n ostic  c ha n ges i n ma na ge me nt  if dia g n ostic res ult (sec o n dar y):   
Referrals t o Ne w Healt hcare Pr o vi ders (i nc. S pecialt y ) 
o  Disease -s pecific treat me nt or me dicati o n C ha n ges (i nc. T y pe a n d Detail)  
o  Disease -s pecific scree ni n g (i m ple me nte d ne w scree ni n g, scree ni n g 
i m ple me nte d f or s us pecte d d x was j ustifie d) 
o  Decisi o ns o n palliati ve care  

 
  1 1  
o  Partici pati o n i n researc h st u d y ( T y pe) 
o  Fa mil y pla n ni n g, c o u nseli n g, or s u p p ort ( T y pe) 
 O utc o me Me as ure Defi niti o ns  
T he f oll o wi n g t y pes of c ha n ge i n ma na ge me nt will be c o nsi dere d.  
•  Rec o m me n de d c ha n ges i n f ut ure disease m o nit ori n g, as d oc u me nte d i n me dical 
rec or ds or base d o n c ha n ges t o pr o vi ders see n or i nter ve nti o ns rec o m me n de d; 
•  C ha n ges i n t he detecti o n a n d/ or ma na ge me nt of tar get c o m plicati o ns (e x. as pirati o n 
p ne u m o nia) as d oc u me nte d i n me dical rec or ds or base d o n c ha n ges t o pr o vi ders see n 
or i nter ve nti o ns rec o m me n de d;  
•  Rec o m me n de d c ha n ges i n m o nit ori n g f or sec o n dar y c o m plicati o ns (e x. ca ncer 
s usce pti bilit y) as d oc u me nte d i n me dical rec or ds or base d o n c ha n ges t o pr o vi ders 
see n or i nter ve nti o ns rec o m me n de d; 
•  C ha n ges t o c o n diti o n s pecific ma na ge me nt (s pecific t hera p y relate d t o t he eti ol o g y 
of t he dia g n osis) as d oc u me nte d i n me dical rec or ds or base d o n c ha n ges t o pr o vi ders 
see n or i nter ve nti o ns rec o m me n de d; 
•  C ha n ges t o s pecific s u p p orti ve i nter ve nti o ns (s u p p orti ve care i nf or me d b y a better 
u n dersta n di n g of t he dia g n osis) as d oc u me nte d i n me dical rec or ds or base d o n 
c ha n ges t o pr o vi ders see n or i nter ve nti o ns rec o m me n de d;  
•  C ha n ges t o palliati ve or e n d -of -life care or a si g nifica nt c ha n ge t o e x pecte d 
o utc o mes (i nf or me d b y a better u n dersta n di n g of t he pr o g n osis) as d oc u me nte d i n 
me dical rec or ds or base d o n c ha n ges t o pr o vi ders see n or i nter ve nti o ns 
rec o m me n de d. 
4. 2  
S afet y E v al u ati o n  
As a mi ni mal -ris k o bser vati o nal st u d y, t he i n vesti gat ors d o n ot i nte n d t o i m ple me nt safet y 
e val uati o ns. Res ults of cli nical testi n g perf or me d c o nc urre ntl y t o st u d y e nr oll me nt will be 
discl ose d b y lice nse d practiti o ners  i n acc or da nce wit h esta blis he d cli nical g ui deli nes . Data 
c ollecti o n fr o m me dical rec or ds a n d prese nts mi ni mal ris ks t o s u bjects.  
5  
S T A TI S TI C A L C O N SI D E R A TI O N S  
5. 1  
A n al ysis Pl a n a n d S a m ple Size Deter mi n ati o n  
 A n al ysis f or Ai m 1  
T he pr o p orti o n of s u bjects w h o ha ve a c ha n ge i n dia g n osis stat us  a n d t he c o n diti o nal 
pr o p orti o n of s u bjects w h o were i m pacte d b y W G S will be calc ulate d f or t he c o h ort, 
wit h 9 5 % c o nfi de nce i nter vals ( 9 5 % CI).  In di vi d uals w h o were recr uite d t o t he 
pre vi o us (ra n d o mize d cr oss o ver) versi o n of t his pr ot oc ol  will be i ncl u de d. 
 A n al ysis f or Ai m 2  
T he fre q ue nc y a n d c o n diti o nal pr o p orti o n of s u bjects w h o recei ve d d o w nstrea m 
c ha n ges i n cli nical ma na ge me nt after a dia g n ostic res ult  t hr o u g h W G S will be 
calc ulate d f or t he c o h ort, wit h 9 5 % c o nfi de nce i nter vals ( 9 5 % CI). T he t y pe of 
d o w nstrea m cli nical c ha n ges will be re p orte d. I n di vi d uals w h o were recr uite d t o t he 

 
  1 2  
pre vi o us (ra n d o mize d cr oss o ver) versi o n of t his pr ot oc ol a n d recei ve d a dia g n osis 
t hr o u g h W G S will be i ncl u de d.  
 
 S a m ple Size Deter mi n ati o n  
 Ai m 1 : D ue t o t he r a pi d c h a n ges i n st a n d ar d of c are, m a ny of t he c o ntr ol ar m 
were i neli gi ble f or p artici p ati o n as a hist oric al c o ntr ol, si nce t hey receive d W G S 
t hr o u g h cli nic al c are. T hese c h a n ges t o st a n d ar d of c are als o hi n dere d st u dy 
e nr oll me nt s a m ple size g o als. T he t ot al s a m ple size t h at w as ac hieve d is N = 8 0 
(i ncl u di n g t he s u bjects e nr olle d i n t he r a n d o mize d c o ntrol ar m). P o wer 
c alc ul ati o ns are n o l o n ger nee de d f or c o m p aris o n t o c o ntr ol ar m.  
 Ai m 2  Refer t o 5. 1. 2 . 
 Missi n g D at a  
T he pr o p orti o n of s u bjects w h o were l ost t o f oll o w -u p will be re p orte d.  
6  
S A F E T Y M A N A G E M E N T  
T he maj or researc h -s pecific ris k ass ociate d wit h t his o bser vati o nal st u d y is t he i na d verte nt 
discl os ure of pr otecte d healt h i nf or mati o n ( P HI) fr o m me dical rec or ds c ollecte d d uri n g t he 
f oll o w-u p peri o d . If a n y u na ntici pate d pr o ble ms relate d t o t he researc h i n v ol vi n g ris ks t o 
s u bjects or ot hers ha p pe n d uri n g t he c o urse of t his st u d y (i ncl u di n g S A Es) t he y will be 
re p orte d t o t he I R B i n acc or da nce wit h C H O P I R B S O P 4 0 8: U na ntici pate d Pr o ble ms 
I n v ol vi n g Ris ks t o S u bjects. A Es t hat are n ot seri o us b ut t hat are n ota ble a n d c o ul d i n v ol ve 
ris ks t o s u bjects will be s u m marize d i n narrati ve or ot her f or mat a n d s u b mitte d t o t he I R B at 
t he ti me of c o nti n ui n g re vie w.  
7  
S T U D Y M A N A G E M E N T  
7. 1  
D at a C ollecti o n a n d M a n a ge me nt  
S u bjec t me dical rec or ds will be ke pt i n l oc ke d file ca bi nets i n t he pri nci pal  i n vesti gat or’s 
office . O nl y t he a p pr o ve d st u d y staff will be a ble t o access t hese rec or ds.  De m o gra p hic  
i nf or mati o n will be ke pt i n a pass w or d-pr otecte d R E D Ca p data base  accessi ble o nl y b y 
a p pr o ve d st u d y staff. W hile we d o n ot a ntici pate t he nee d t o re g ularl y c ollect pare ntal 
me dical rec or ds, t his w o ul d be ha n dle d i n a si milar fas hi o n.  
Wit h dra wal fr o m t he st u d y is per mitte d at a n y ti me a n d w o ul d res ult i n re m o val of a n y 
i de ntif yi n g i nf or mati o n fr o m rec or de d data bases.  
7. 2  
C o nfi de nti alit y  
N o P HI  will be use d f or f ut ure st u d y wit h o ut first o btai ni n g I R B a p pr o val. A  data use 
a gree me nt  ( D U A) will be e xec ute d bet wee n t he pr o vi der of t he data a n d a n y reci pie nt 
researc hers (i ncl u di n g t h ose at C H O P) bef ore s hari n g a li mite d dataset . F ull y de-i de ntifie d 
data  ma y be s hare d o n a case -b y -case basis.  

 
  1 3  
7. 3  
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
 Ris k Assess me nt , Ge ner al C o nsi der ati o ns 
T his o bser vati o nal st u d y is c o nsi dere d t o i n v ol ve n o greater t ha n a mi ni mal  a m o u nt of ris k. 
T he pri mar y ris k of st u d y partici pati o n i n v ol ves breac h of  c o nfi de ntialit y  d ue t o c ollecti o n, 
a nal ysis, a n d/ or rete nti o n of P HI  fr o m s u bject me dical rec or ds . 
 Ps yc h ol o gic al H ar ms  
All ge netic testi n g d o ne i n t his st u d y is part of t he c hil d’s cli nical care. We d o n ot a ntici pate 
a n y ps yc h ol o gical har ms . T his pr ot oc ol ma y gi ve false h o pe; t he pri nci pal i n vesti gat or a n d 
ge netic c o u nsel ors will atte m pt t o a v oi d t his.   
 Discri mi n ati o n  
T o t he f ullest e xte nt p ossi ble, t he i n vesti gat ors will n ot discl ose t o t hir d parties a n y 
i nf or mati o n a b o ut t he partici pa nts wit h o ut t heir e x presse d c o nse nt. 
 C o nfi de nti alit y of Me dic al I nf or m ati o n a n d S a m ples  
U p o n e nr oll me nt i n C H O P I R B 1 4 -0 1 1 2 3 6 f or preli mi nar y assess me nt of eli gi bilit y , 
ca n di dates will recei ve a u ni q ue al p ha n u merical st u d y i de ntifier (e x. L S_ 0 7 8)  ge nerate d b y 
st u d y staff. T he ke y will be l ocate d i n a pass w or d -pr otecte d R E D Ca p data base, accessi ble 
o nl y b y a p pr o ve d  st u d y staff. Na mes are mai ntai ne d i n t his data base i n or der t o pr o vi de 
patie nts wit h cli nicall y rele va nt i nf or mati o n ge nerate d fr o m t his st u d y. Wit h dra wal fr o m t he 
st u d y w o ul d res ult i n re m o val of a n y i de ntif yi n g i nf or mati o n fr o m rec or de d data bases a n d 
destr ucti o n of a n y bl o o d sa m ples.  
 P ote nti al Be nefits  
St u d y partici pati o n is n ot  i nte n de d t o c o nfer a n y direct be nefit  t o s u bjects. T he i n vesti gat ors 
are c o nfi de nt t hat t he k n o wle d ge glea ne d fr o m t his st u d y will s u p p ort wi der i m ple me ntati o n 
a n d access t o w h ole ge n o me se q ue nci n g . 
 Ris k -Be nefit Assess me nt  
T his is a n o m ore t ha n mi ni mal ris k pr ot oc ol, w here ris ks e nc o u ntere d are t he sa me as t h ose 
e nc o u ntere d i n r o uti ne cli nical care  wit h t he a d diti o n of t h ose ris ks relate d t o me dical rec or d 
re vie w.  
7. 4  
Recr uit me nt Str ate g y  
Ca n di dates  will ge nerall y be i de ntifie d d uri n g t heir r o uti ne cli nical care at  C H O P  a n d ot her 
o utsi de i nstit uti o ns. I nf or mati o n a b o ut t he st u d y has bee n p oste d o n Cli nical Trials. g o v 
(N C T 0 2 6 9 9 1 9 0 ), a n d ma y be s hare d wit h cli nicia ns a n d/ or i n vesti gat ors at C H O P a n d ot her 
o utsi de i nstit uti o ns w h o r o uti nel y e nc o u nter patie nts wit h s us pecte d le u k o d ystr o p hies or 
ot her ge netic dis or ders affecti n g t he w hite matter of t he brai n.  
Referri n g pr o vi ders will as k t he st u d y ca n di date’s fa mil y t o c o m plete a R E D Ca p -base d 
‘ Referral S ur ve y’ use d b y t he C H O P Le u k o d ystr o p h y Ce nter t o c ollect  basic c o ntact a n d 
cli nical i nf or mati o n fr o m i n di vi d uals/fa milies i ntereste d i n sc he d uli n g a cli nical a p p oi nt me nt 
a n d/ or partici pati n g i n a researc h st u d y.  

 
  1 4  
7. 5  
I nf or me d C o nse nt/ Asse nt a n d HI P A A A ut h oriz ati o n 
I nf or me d c o nse nt will t y picall y be d oc u me nte d i n t he c o nte xt of a s u bject’s cli nical 
e val uati o n at C H O P . T he s u bject will be gi ve n a t h or o u g h e x pla nati o n of t he st u d y, 
i ncl u di n g t he p ur p ose, pr oce d ures, ris ks a n d be nefits of partici pati o n, c o nfi de ntialit y, 
pr oce d ures f or wit h dra wal, a n d c o ntact i nf or mati o n f or st u d y pers o n nel. Fa milies will be 
i nf or me d t hat t heir me dical care at t hat i nstit uti o n will n ot be affecte d if t he y c h o ose n ot t o 
partici pate i n t he pr o p ose d researc h. If t he s u bject is i ntereste d i n e nr olli n g, a q ualifie d 
me m ber of t he st u d y tea m will e ns ure t hat i nf or me d c o nse nt is f ull y d oc u me nte d usi n g 
a p pr o ve d versi o ns of t he i nf or me d c o nse nt f or m (I C F).  
 
Met h o ds ot her t ha n a face -t o-face c o nse nt i nter vie w ma y be perf or me d if an eli gi ble s u bject 
is u na ble t o visit a partici pati n g st u d y site. I n t his sce nari o, st u d y staff will e ns ure t hat t his 
a p pr oac h all o ws f or a n a de q uate e xc ha n ge of i nf or mati o n a n d d oc u me ntati o n, a n d a met h o d 
t o e ns ure t hat t he si g ner of t he c o nse nt f or m is t he pers o n wh o pla ns t o e nr oll as a s u bject i n 
t he cli nical i n vesti gati o n or is le gall y a ut h orize d t o pr o vi de a si g nat ure o n be half of t he 
s u bject. T he I C F will be se nt t o t he s u bject b y p ostal mail, facsi mile, or e mail, a n d t he 
c o nse nt i nter vie w will t he n be c o n d ucte d b y tele p h o ne or a C H O P -a p pr o ve d vi de o 
c o nfere nci n g t o ol s uc h as We b E x, Bl ueJea ns, or Micr os oft Tea ms  after e ns uri n g t hat  t he 
s u bject has recei ve d a c o p y of t he i nf or me d  c o nse nt f or m  f or refere nce d uri n g t he 
disc ussi o n.  
 
F oll o wi n g  t he c o nse nt disc ussi o n, t he s u bject will si g n a n d date t he c o nse nt f or m a n d ret ur n 
t he d oc u me nt t o a n a ut h orize d me m ber of t he S t u d y T ea m b y p ostal mail, facsi mile, e mail, 
or b y u pl oa di n g it t o a C H O P -a p pr o ve d  file h osti n g ser vice s uc h as B o x, O ne Dri ve, G o o gle 
Dri ve, etc.  
 
A s u bject ma y als o be i n vite d t o si g n t he i nf or me d c o nse nt f or m electr o nicall y usi n g a n 
eletr o nic  si g nat ure via A d o be Si g n or  D oc u Si g n, or a n y ot her cl o u d-base d electr o nic 
si g nat ure platf or m t hat has bee n a p pr o ve d f or use b y t he C H O P Researc h I nstit ute. I n s uc h a 
case, f or ms  will be se nt f or si g nat ure via sec ure e mail. U p o n c o m pleti o n of all  re q uire d 
fiel ds, t he d oc u me nt will be  a ut o maticall y ret ur ne d t o a desi g nate d me m ber of t he st u d y 
tea m f or re vie w a n d fi nal si g nat ure. A  f ull y e xec ute d c o p y will t he n b e u pl oa de d t o t he 
s u bject’s researc h c hart i n R E D Ca p a n d ret ur ne d t o t he s u bject f or f ut ure refere nce. 
 
S u bjects w h o t ur n 1 8 w hile e nr olle d i n t he st u d y will be as ke d t o si g n t he c urre ntl y a p pr o ve d 
versi o n of t he c o nse nt f or m at t heir ne xt st u d y visit after t he s u bject reac hes t he a ge of 
maj orit y ( or, if c o g niti vel y i m paire d, t heir le gall y a ut h orize d re prese ntati ve).  
 
All reas o na ble eff orts will be ma de t o acc o m m o date n o n -E n glis h s pea ki n g s u bject s. If a 
Li mite d E n glis h Pr oficie nc y ( L E P) s u bject  is a ble t o visit a partici pati n g st u d y site f or 
e nr oll me nt, a certifie d cli nical i nter preter will ge nerall y be a vaila ble t o facilitate t he ‘ S h ort 
F or m C o nse nt’ pr ocess, w hic h has bee n a p pr o ve d f or use i n t his st u d y.  T he st u d y tea m will 
d oc u me nt t he i nter preter’s e m pl o yee I D n u m ber.  
 
If a ‘ S h ort F or m C o nse nt’ f or m is n ot a vaila ble i n a partic ular s u bject’s nati ve la n g ua ge, t he 
st u d y tea m will  s u b mit a n a me n d me nt t o t he C H O P I R B. T he a me n d me nt will i ncl u de a 

 
  1 5  
tra nslate d versi o n of ‘ S h ort F or m C o nse nt’ f or m i n t he la n g ua ge nee de d, al o n g wit h a 
certificate of tra nslati o n , a n d will nee d t o be a p pr o ve d pri or t o e nr olli n g t he s u bject.  
T he st u d y tea m will o btai n asse nt fr o m a d ults wit h di mi nis he d ca pacit y a n d c hil dre n ol der 
t ha n 7 years of a ge w he ne ver p ossi ble. If s u bjects u n der t he a ge of 1 8 years are u na ble t o 
pr o vi de asse nt , beca use t he y are eit her t o o y o u n g (less t ha n 7  years of a ge) , or t heir disease 
i nterferes wit h t heir a bilit y t o pr o vi de asse nt, t his reas o n will be d oc u me nte d o n t he 
c o nse nt/asse nt f or ms.  
U p o n occasi o n, s u bjects ma y bec o me l ost t o f oll o w -u p. T his a p plies i n partic ular t o re -
c o nse nt i n patie nts o ver t he a ge of 1 8. A s u bject will be c o nsi dere d l ost t o f oll o w u p if 3 
atte m pts b y p h o ne or e mail o n se parate da ys a n d se parate ti mes a n d har d c o p y letter if 
a d dress is c urre nt are u ns uccessf ul i n reac hi n g t he s u bject.  
 
 S h ort F or m C o nse nt Pr ocess Re q uiri n g Tele p h o nic I nter pret ati o n Ser vices  
 
If a certifie d i nter preter is n ot p h ysicall y a vaila ble at t he ti me of a site visit, or if a 
L E P  s u bject is u na ble t o tra vel t o a partici pati n g site, a n a ut h orize d tele p h o nic 
i nter pretati o n ser vice (e. g., ‘I nter pre Tal k’) will be use d t o facilitate t he ‘ S h ort F or m 
C o nse nt’ pr ocess.   
 
A  me m ber of t he st u d y tea m will s hare a n a p pr o ve d ‘S h ort F or m C o nse nt ’ d oc u me nt 
i n a la n g ua ge nati ve t o t he s u bject pri or t o t he c o nse nt i nter vie w. U p o n c o ncl usi o n of 
t he c o nse nt i nter vie w, t he s u bject will si g n t he ‘ S h ort F or m C o nse nt’ f or m, a n d a n 
i m partial wit ness/i nter preter w h o s pea ks b ot h t he s u bject’s nati ve la n g ua ge a n d 
E n glis h will be as ke d t o si g n t he ‘ S h ort F or m C o nse nt’ f or m a n d St u d y S u m mar y 
D oc u me nt”. T he wit ness/i nter preter's i n v ol ve me nt ( w he n n ot prese nt i n pers o n) will 
be d oc u me nte d.  
 
 HI P A A Attest ati o n f or t he Use of Dece de nt P HI  
A wai ver of HI P A A A ut h orizati o n has bee n re q ueste d t o use cli nical data o btai ne d fr o m 
decease d i n di vi d uals, as t his researc h will als o utilize t he P HI of dece de nts. I n acc or da nce 
wit h 4 5 C F R 1 6 4. 5 1 2(i)( 1)(iii), t he use or discl os ure bei n g s o u g ht is s olel y f or researc h o n 
t he pr otecte d healt h i nf or mati o n of dece de nts, t he pr otecte d healt h i nf or mati o n bei n g s o u g ht 
is necessar y f or t he researc h, a n d, at t he re q uest of t he c o vere d e ntit y ( C H O P), 
d oc u me ntati o n of t he deat h of t he i n di vi d uals a b o ut w h o m i nf or mati o n is bei n g s o u g ht ca n 
be pr o vi de d. Si nce dece de nts are n o l o n ger h u ma n s u bjects, t heir data/sa m ples i ncl u de d i n 
t his researc h will n ot be i ncl u de d i n t he e nr oll me nt n u m bers f or t his st u d y a n d researc h 
acti vities usi n g t hese sa m ples/ data will n ot be re p orte d as part of t he c o nti n ui n g re vie w. 
7. 6  
P a y me nt t o S u bjects/ F a milies  
T here will be n o pa y me nt or gifts t o s u bjects or fa milies as part of t his pr ot oc ol . 

 
  1 6  
8  
P U B LI C A TI O N  
As t his st u d y ma y i n v ol ve fi n di n gs of n o vel ge nes i m plicate d i n disease, i de ntificati o n of a 
s pecific i n di vi d ual fr o m t he dia g n osis c o ul d be discer ne d i n p u blicati o ns or prese ntati o ns 
alt h o u g h t his is u nli kel y i n a c o h ort of 1 0 0 partici pa nts a n d t heir bi ol o gical pare nts. It is 
d o u btf ul t hat a n y de m o gra p hic i nf or mati o n c o ul d i de ntif y a n i n di vi d ual.  
 
 

 
  1 7  
 
9  
R E F E R E N C E S  
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le u k o d ystr o p hies: a gla nce at glial f u ncti o ns. C urre nt ne ur ol o gy a n d ne ur oscie nce re p orts  
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3.  
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T he b ur de n of i n herite d le u k o d ystr o p hies i n c hil dre n. Ne ur ol o gy  2 0 1 0; 7 5 ( 8): 7 1 8-2 5.  
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va n der K naa p M S, Breiter S N, Nai d u S, Hart A A, Val k J. Defi ni n g a n d cate g orizi n g 
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Se mi n ars i n pe di atric ne ur ol o gy  2 0 1 2; 1 9 ( 4): 2 1 9-2 3.  
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Ric har ds J, K or ge ns ki E K, Sri vasta va R, B o n k o ws k y J L. C osts of t he dia g n ostic 
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Ba ms ha d MJ, N g S B, Bi g ha m A W, et al. E x o me se q ue nci n g as a t o ol f or Me n delia n 
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1 0.  
N g S B, Nic kers o n D A, Ba ms ha d MJ, S he n d ure J. Massi vel y parallel se q ue nci n g a n d 
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Ma kr yt ha nasis P, Nelis M, Sa nt o ni F A, et al. Dia g n ostic E x o me Se q ue nci n g t o 
El uci date t he Ge netic Basis of Li kel y Recessi ve Dis or ders i n C o nsa n g ui ne o us Fa milies. 
H u m M ut at  2 0 1 4.  
1 2.  
Ta yl or R W, P yle A, Griffi n H, et al. Use of w h ole -e x o me se q ue nci n g t o deter mi ne 
t he ge netic basis of m ulti ple mit oc h o n drial res pirat or y c hai n c o m ple x deficie ncies. J A M A : 
t he j o ur n al of t he A meric a n Me dic al Ass oci ati o n 2 0 1 4; 3 1 2 ( 1): 6 8-7 7.  
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Sri vasta va S, C o he n J S, Ver n o n H, et al. Cli nical W h ole E x o me Se q ue nci n g i n C hil d 
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1 4.  
F o gel B L, Lee H, Dei g na n J L, et al. E x o me Se q ue nci n g i n t he Cli nical Dia g n osis of 
S p ora dic or Fa milial Cere bellar Ata xia. J A M A ne ur ol o gy  2 0 1 4.  
1 5.  
Ya n g Y, M uz n y D M, Rei d J G, et al. Cli nical w h ole -e x o me se q ue nci n g f or t he 
dia g n osis of me n delia n dis or ders. T he Ne w E n gl a n d j o ur n al of me dici ne  2 0 1 3; 3 6 9 ( 1 6): 
1 5 0 2 -1 1.  
1 6.  
Bea ulie u C L, Maje ws ki J, Sc h wartze ntr u ber J, et al. F O R G E Ca na da C o ns orti u m: 
o utc o mes of a 2 -year nati o nal rare -disease ge ne -disc o ver y pr oject. A meric a n j o ur n al of 
h u m a n ge netics  2 0 1 4; 9 4 ( 6): 8 0 9-1 7.  

 
  1 8  
1 7.  
de Li gt J, Wille mse n M H, va n B o n B W, et al. Dia g n ostic e x o me se q ue nci n g i n 
pers o ns wit h se vere i ntellect ual disa bilit y. T he Ne w E n gl a n d j o ur n al of me dici ne  2 0 1 2; 
3 6 7 ( 2 0): 1 9 2 1-9.  
1 8.  
Sc hiff ma n n R, F o gli A, Va n der K naa p M S, B oes pfl u g -Ta n g u y O. C hil d h o o d Ata xia 
wit h Ce ntral Ner v o us S yste m H y p o m yeli nati o n/ Va nis hi n g W hite Matter. I n: Pa g o n R A, 
A da m M P, Bir d T D, D ola n C R, F o n g C T, Ste p he ns K, e ds. Ge ne Re vie ws. Seattle ( W A); 
1 9 9 3.  
1 9.  
va n der K naa p M S, Bart h P G, Ga breels FJ, et al. A ne w le u k oe nce p hal o pat h y wit h 
va nis hi n g w hite matter. Ne ur ol o gy  1 9 9 7; 4 8 ( 4): 8 4 5-5 5.  
2 0.  
Lee g water P A, Ver me ule n G, K o nst A A, et al. S u b u nits of t he tra nslati o n i nitiati o n 
fact or eI F 2 B are m uta nt i n le u k oe nce p hal o pat h y wit h va nis hi n g w hite matter. N at ure 
ge netics  2 0 0 1; 2 9 ( 4): 3 8 3-8.  
2 1.  
Ti m m o ns M, Ts o k os M, Asa b M A, et al. Peri p heral a n d ce ntral h y p o m yeli nati o n 
wit h h y p o g o na d otr o pic h y p o g o na dis m a n d h y p o d o ntia. Ne ur ol o gy  2 0 0 6; 6 7 ( 1 1): 2 0 6 6-9.  
2 2.  
Ber nar d G, C h o uer y E, P ut orti M L, et al. M utati o ns of P O L R 3 A e nc o di n g a catal ytic 
s u b u nit of R N A p ol y merase P ol III ca use a recessi ve h y p o m yeli nati n g le u k o d ystr o p h y. 
A meric a n j o ur n al of h u m a n ge netics  2 0 1 1; 8 9 ( 3): 4 1 5-2 3.  
2 3.  
Da o u d H, Tetrea ult M, Gi bs o n W, et al. M utati o ns i n P O L R 3 A a n d P O L R 3 B are a 
maj or ca use of h y p o m yeli nati n g le u k o d ystr o p hies wit h or wit h o ut de ntal a b n or malities 
a n d/ or h y p o g o na d otr o pic h y p o g o na dis m. J o ur n al of me dic al ge netics  2 0 1 3; 5 0 ( 3): 1 9 4-7.  
2 4.  
va n der K naa p M S, va n der V o or n P, Bar k h of F, et al. A ne w le u k oe nce p hal o pat h y 
wit h brai nste m a n d s pi nal c or d i n v ol ve me nt a n d hi g h lactate. A n n als of ne ur ol o gy  2 0 0 3; 
5 3 ( 2): 2 5 2-8.  
2 5.  
Sc he per G C, va n der Kl o k T, va n A n del RJ, et al. Mit oc h o n drial as part yl -t R N A 
s y nt hetase deficie nc y ca uses le u k oe nce p hal o pat h y wit h brai n ste m a n d s pi nal c or d 
i n v ol ve me nt a n d lactate ele vati o n. N at ure ge netics  2 0 0 7; 3 9 ( 4): 5 3 4-9.  
2 6.  
Lee g water P A, Y ua n B Q, va n der Stee n J, et al. M utati o ns of M L C 1 ( KI A A 0 0 2 7), 
e nc o di n g a p utati ve me m bra ne pr otei n, ca use me gale nce p halic le u k oe nce p hal o pat h y wit h 
s u bc ortical c ysts. A meric a n j o ur n al of h u m a n ge netics  2 0 0 1; 6 8 ( 4): 8 3 1-8.  
2 7.  
L o pez -Her na n dez T, Ri d der M C, M o nt oli o M, et al. M uta nt Glial C A M ca uses 
me gale nce p halic le u k oe nce p hal o pat h y wit h s u bc ortical c ysts, be ni g n fa milial macr oce p hal y, 
a n d macr oce p hal y wit h retar dati o n a n d a utis m. A meric a n j o ur n al of h u m a n ge netics  2 0 1 1; 
8 8 ( 4): 4 2 2-3 2.  
2 8.  
Stee n we g M E, Va n der ver A, Ce ule ma ns B, et al. N o vel i nfa ntile -o nset 
le u k oe nce p hal o pat h y wit h hi g h lactate le vel a n d sl o w i m pr o ve me nt. Arc hives of ne ur ol o gy  
2 0 1 2; 6 9 ( 6): 7 1 8-2 2.  
2 9.  
Stee n we g M E, G hezzi D, Haac k T, et al. Le u k oe nce p hal o pat h y wit h t hala m us a n d 
brai nste m i n v ol ve me nt a n d hi g h lactate ' L T B L' ca use d b y E A R S 2 m utati o ns. Br ai n : a 
j o ur n al of ne ur ol o gy 2 0 1 2; 1 3 5 ( Pt 5): 1 3 8 7-9 4.  
3 0.  
Taft RJ, Va n der ver A, Le ve nter RJ, et al. M utati o ns i n D A R S ca use 
h y p o m yeli nati o n wit h brai n ste m a n d s pi nal c or d i n v ol ve me nt a n d le g s pasticit y. A meric a n 
j o ur n al of h u m a n ge netics 2 0 1 3; 9 2 ( 5): 7 7 4-8 0.  
3 1.  
Si m o ns C, W olf NI, Mc Neil N, et al. A de n o v o m utati o n i n t he beta -t u b uli n ge ne 
T U B B 4 A res ults i n t he le u k oe nce p hal o pat h y h y p o m yeli nati o n wit h atr o p h y of t he basal 
ga n glia a n d cere bell u m. A meric a n j o ur n al of h u m a n ge netics  2 0 1 3; 9 2 ( 5): 7 6 7-7 3.  

 
  1 9  
3 2.  
Va n der ver A, Hat h o ut Y, Malet k o vic J, et al. Se nsiti vit y a n d s pecificit y of decrease d 
C S F asial otra nsferri n f or eI F 2 B -relate d dis or der. Ne ur ol o gy  2 0 0 8; 7 0 ( 2 3): 2 2 2 6-3 2.  
3 3.  
Va n der ver A, Sc hiff ma n n R, Ti m m o ns M, et al. Decrease d asial otra nsferri n i n 
cere br os pi nal fl ui d of patie nts wit h c hil d h o o d -o nset ata xia a n d ce ntral ner v o us s yste m 
h y p o m yeli nati o n/ va nis hi n g w hite matter disease. Cli nic al c he mistry  2 0 0 5; 5 1 ( 1 1): 2 0 3 1-4 2.  
3 4.  
Rice G, Patric k T, Par mar R, et al. Cli nical a n d m olec ular p he n ot y pe of Aicar di -
G o utieres s y n dr o me. A meric a n j o ur n al of h u m a n ge netics  2 0 0 7; 8 1 ( 4): 7 1 3-2 5.  
3 5.  
Rice GI, B o n d J, Asi p u A, et al. M utati o ns i n v ol ve d i n Aicar di -G o utieres s y n dr o me 
i m plicate S A M H D 1 as re g ulat or of t he i n nate i m m u ne res p o nse. N at ure ge netics  2 0 0 9; 
4 1 ( 7): 8 2 9-3 2.  
3 6.  
M oc hel F, E n gel ke U F, Barrita ult J, et al. Ele vate d C S F N -acet ylas part yl gl uta mate i n 
patie nts wit h free sialic aci d st ora ge diseases. Ne ur ol o gy ; 7 4 ( 4): 3 0 2-5.  
3 7.  
M oc hel F, Se del F, Va n der ver A, et al. Cere bellar ata xia wit h ele vate d cere br os pi nal 
free sialic aci d ( C A F S A). Br ai n : a j o ur n al of ne ur ol o gy  2 0 0 9; 1 3 2 ( Pt 3): 8 0 1-9.  
3 8.  
G or os pe J R, Si n g hal B S, Kai n u T, et al. I n dia n A gar wal me gale nce p halic 
le u k o d ystr o p h y wit h c ysts is ca use d b y a c o m m o n M L C 1 m utati o n. Ne ur ol o gy  2 0 0 4; 6 2 ( 6): 
8 7 8 -8 2.  
3 9.  
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