RESEARCH ARTICLE
Nosology and Classification of Genetic SkeletalDisorders: 2010 RevisionMatthew L. Warman,1 Valerie Cormier-Daire,2 Christine Hall,3 Deborah Krakow,4,5 Ralph Lachman,4
Martine LeMerrer,2 Geert Mortier,6 Stefan Mundlos,7 Gen Nishimura,8 David L. Rimoin,4
Stephen Robertson,9 Ravi Savarirayan,10 David Sillence,11 Juergen Spranger,12 Sheila Unger,12,13
Bernhard Zabel,12 and Andrea Superti-Furga12,14*1Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, The Howard Hughes Medical Institute, Children’s Hospital, Boston,
Massachusetts2Department of Genetics and INSERM U781, Paris Descartes University, Hôpital Necker Enfants Malades, Paris, France3Institute of Child Health, University of London, London, UK4Medical Genetics Institute, Steven Spielberg Building, Cedars-Sinai Medical Center, Los Angeles, California5Departments of Orthopaedic Surgery and Human Genetics, UCLA, Los Angeles, California6Department of Medical Genetics, University Hospital of Antwerp, University of Antwerp, Edegem, Belgium7Institut f€ur Medizinische Genetik, Charit�e Universit€atsmedizin Berlin, Max-Planck-Institut f€ur Molekulare Genetik, Berlin, Germany8Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Fuchu, Tokyo, Japan9Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand10Murdoch Children’s Research Institute, Royal Children’s Hospital, Department of Paediatrics, University of Melbourne, Victoria, Australia11Discipline of Genetic Medicine, The Children’s Hospital at Westmead Clinical School, The University of Sydney, Westmead, Australia12Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany13Medical Genetics Service, University of Lausanne, CHUV—Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland14Department of Pediatrics, University of Lausanne, CHUV—Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Received 16 December 2010; Accepted 30 December 2010
Genetic disorders involving the skeletal system arise through
disturbances in the complex processes of skeletal development,
growth and homeostasis and remain a diagnostic challenge
because of their variety. The Nosology and Classification of
Genetic Skeletal Disorders provides an overview of recognized
diagnostic entities and groups them by clinical and radiographic
features and molecular pathogenesis. The aim is to provide the
Genetics, Pediatrics and Radiology community with a list of
recognized genetic skeletal disorders that can be of help in the
diagnosis of individual cases, in the delineation of novel disor-
ders, and in building bridges between clinicians and scientists
interested in skeletal biology. In the 2010 revision, 456 condi-
tions were included and placed in 40 groups defined by molecu-
lar, biochemical, and/or radiographic criteria. Of these
conditions, 316 were associated with mutations in one or more
of 226 different genes, ranging from common, recurrent muta-
tions to ‘‘private’’ found in single families or individuals. Thus,
the Nosology is a hybrid between a list of clinically defined
The 9th ISDS meeting and the Nosology workshop were held in Boston in
July 2009 and supported by The Manton Center for Orphan Disease
Research, Children’s Hospital, Boston, Massachusetts; Children’s
Orthopaedic Surgery Foundation, Inc., Boston, Massachusetts; The
Osteogenesis Imperfecta Foundation, Gaithersburg, Maryland;
Biomarin, Novato, California; and Enobia Pharma, Montreal, Quebec,
Canada. The 2010 Nosology tables are available online at the International
Skeletal Dysplasia Society web site (www.isds.ch).
*Correspondence to:
Andrea Superti-Furga, Centre Hospitalier Universitaire Vaudois (CHUV),
Av. Decker, 2, 1011 Lausanne, Switzerland. E-mail: [email protected]
Published online 15 March 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.a.33909
How to Cite this Article:Warman ML, Cormier-Daire V, Hall C,
Krakow D, Lachman R, LeMerrer M, Mortier
G, Mundlos S, Nishimura G, Rimoin DL,
Robertson S, Savarirayan R, Sillence D,
Spranger J, Unger S, Zabel B, Superti-Furga A.
2011. Nosology and classification of genetic
skeletal disorders: 2010 revision.
Am J Med Genet Part A 155:943–968.
� 2011 Wiley-Liss, Inc. 943
disorders, waiting for molecular clarification, and an annotated
database documenting the phenotypic spectrum produced by
mutations in a given gene. The Nosology should be useful for the
diagnosis of patients with genetic skeletal diseases, particularly
in view of the information flood expected with the novel se-
quencing technologies; in the delineation of clinical entities and
novel disorders, by providing an overview of established noso-
logic entities; and for scientists looking for the clinical correlates
of genes, proteins and pathways involved in skeletal biology.
� 2011 Wiley-Liss, Inc.
Key words: skeletal genetics; osteochondrodysplasias; nosology;dysostoses; molecular basis of disease
INTRODUCTION
In the 1960s, accumulating evidence that genetic skeletal disorders
were clinically and genetically heterogeneous prompted a group of
international experts to prepare a document to reach an agreement
on the nomenclature of what was then called ‘‘constitutional (or
intrinsic) disorders of bone’’ [1970, 1971a,b,c,d; McKusick and
Scott, 1971]. The ‘‘Nomenclature’’ was meant to bring together
experts in radiology, clinical genetics, and pediatrics to agree on the
denomination and classification of skeletal disorders, syndromes
and metabolic diseases that were being newly described. Revisions
have been prepared in 1977, 1983, 1992, and 1997 [1978, 1979, 1983,
1998, Rimoin, 1979; Spranger, 1992; Lachman, 1998]. Following
the establishment of the International Skeletal Dysplasia Society
(ISDS) in 1999, and to cope with the increasing complexity of
information, revisions of the Nosology have been delegated to an
expert group nominated ad hoc within the ISDS to ensure an
adequate representation of clinical, radiological and molecular
expertise (2001 and 2006 revisions) [Hall, 2002; Superti-Furga and
Unger, 2007].
METHODS
The Nosology Group of the International Skeletal Dysplasia Society
met in August 2009. A consensus was reached for changes to be
made to the grouping of disorders and about the inclusion of
individual disorders. The drafts were circulated after the meeting
and an effort was made to monitor recent publications up to
November 2010. The criteria used for inclusion of individual
disorders were unchanged from the previous revision. They were:
(1) Significant skeletal involvement, corresponding to the defini-
tion of skeletal dysplasias, metabolic bone disorders, dysos-
toses, and skeletal malformation and/or reduction syndromes.
(2) Publication and/or listing in MIM (meaning that observations
should not find their way into the Nosology before they achieve
peer-reviewed publication status).
(3) Genetic basis proven by pedigree or very likely based on
homogeneity of phenotype in unrelated families.
(4) Nosologic autonomy confirmed by molecular or linkage anal-
ysis and/or by the presence of distinctive diagnostic features
and of observation in multiple individuals or families.
RESULTS
Four hundred fifty-six different conditions were included and
placed in 40 groups defined by molecular, biochemical and/or
radiographic criteria. Of these conditions, 316 (2006 revision: 215)
were associated with one or more of 226 (2006 revision: 140)
different genes. The results are presented in Table I. Within a
group, disorders with known molecular basis have been listed
preceding those with lesser degree of evidence; however, variants
of the same disorder have been kept together.
The organization of groups has been further changed in com-
parison to the 2006 version. Two new groups based on a common
affected molecule or biochemical pathway have been created
(TRPV4 group and Aggrecan group). The TRPV4 group includes
disorders that are relatively common and that constitute a new
prototypic spectrum ranging from mild to lethal. Aggrecan is one of
the important structural molecules in cartilage and it would not be
surprising if more disorders would find their way into this group in
the future. Thus, groups 1–8 are based on a common underlyinggene or pathway.
Groups 9–17 are based on the localization of radiographicchanges to specific bone structures (vertebrae, epiphyses, meta-
physes, diaphysis, or combination thereof) or of the involved
segment (rhizo, meso, or acro). Groups 18–20 are defined bymacroscopic criteria in combination with clinical features (bent
bones, slender bones, presence of multiple dislocations). Groups
21–25 and 28 take into account features of mineralization(increased or reduced bone density, impaired mineralization,
stippling, osteolysis). Group 27 encompasses the large group of
lysosomal disorders with skeletal involvement. Group 29 comprises
disorders with so-called abnormal (previously ‘‘anarchic’’) devel-
opment of skeletal components such as exostoses, ecnhondromas,
and ectopic calcification. It is particularly heterogeneous and may
need to be revised in the future with the help of newer molecular
data.
Group 23, comprising the osteopetrosis (OP) variants and
related disorders, has been expanded following the identification
of distinct genetic defects in various variants of osteopetrosis. The
diversity of molecular mechanisms involved and the presence of
clinical, biochemical and/or histologic features that distinguish
between the various OP forms justify the subdivision of the ‘‘OP
phenotype’’ in the many subtypes.
Group 25 (Osteogenesis Imperfecta and decreased bone density
group) has had special attention. The Sillence classification, pub-
lished 30 years ago, provided a first systematic clinical classification
and made correlations to the inheritance pattern of individual
clinical types [Sillence and Rimoin, 1978; Sillence et al., 1979a,b].
Today, a surprising genetic complexity of the molecular bases of OI
has been revealed, and at the same time the extensive phenotypic
variation arising from single loci has been documented clearly. It
seemed therefore untenable to try and maintain tight correlations
between ‘‘Sillence types’’ and their molecular basis. It was agreed
upon to retain the Sillence classification as the prototypic and
universally accepted way to classify the degree of severity in OI; and
to free the Sillence classification from any direct molecular refer-
ence. Thus, the many genes that may cause osteogenesis imperfecta
have been listed separately. The proliferation of ‘‘OI types’’ to reflect
944 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TAB
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WARMAN ET AL. 945
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946 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
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sloc
atio
ns8
.TR
PV4
grou
pM
etat
ropi
cdy
spla
sia
AD1
56
53
01
2q2
4.1
TRPV
4Tr
ansi
ent
rece
pto
rpo
ten
tial
cati
onch
ann
el,
subf
amily
V,m
emb
er4
Incl
ud
esle
thal
and
non
-leth
alfo
rms
Spon
dylo
epim
etap
hyse
aldy
spla
sia,
Mar
otea
uxty
pe(P
seud
o–M
orqu
iosy
ndr
ome
type
2)
AD1
84
09
51
2q2
4.1
TRPV
4Tr
ansi
ent
rece
pto
rpo
ten
tial
cati
onch
ann
el,
subf
amily
V,m
emb
er4
Spon
dylo
met
aphy
seal
dysp
lasi
a,K
ozlo
wsk
ity
peAD
18
42
52
12
q24
.1TR
PV4
Tran
sien
tre
cep
tor
pote
nti
alca
tion
chan
nel
,su
bfam
ilyV,
mem
ber
4B
rach
yolm
ia,
auto
som
aldo
min
ant
type
AD1
13
50
01
2q2
4.1
TRPV
4Tr
ansi
ent
rece
pto
rpo
ten
tial
cati
onch
ann
el,
subf
amily
V,m
emb
er4
Fam
ilial
digi
tal
arth
ropa
thy
wit
hbr
achy
dact
yly
AD6
06
83
51
2q2
4.1
TRPV
4Tr
ansi
ent
rece
pto
rpo
ten
tial
cati
onch
ann
el,
subf
amily
V,m
emb
er4
9.
Shor
t-ri
bsdy
spla
sias
(wit
hor
wit
hout
poly
dact
yly)
grou
pCh
ondr
oect
oder
mal
dysp
lasi
a(E
llis–
van
Crev
eld)
AR2
25
50
04
p16
EVC1
EvC
gen
e1
4p1
6EV
C2Ev
Cge
ne
2Sh
ort
rib—
poly
dact
yly
syn
drom
e(S
RPS
)ty
pe1
/3(S
aldi
no-
Noo
nan
/Ve
rma-
Nau
mof
f)
AR2
63
51
01
1q2
2.3
DYN
C2H
1D
ynei
n,
cyto
pla
smic
2,
heav
ych
ain
1
SRPS
type
1/3
(Sal
din
o-N
oon
an/
Verm
a-N
aum
off)
AR2
63
51
03
q25
.33
IFT8
0In
trafl
agel
lar
tran
spor
t8
0(h
omol
ogof
)SR
PSty
pe1
/3(S
aldi
no-
Noo
nan
/Ve
rma-
Nau
mof
f)AR
26
35
10
Un
linke
dto
eith
erD
YNC2
H1
orIF
T80
SRPS
type
2(M
ajew
ski)
AR2
63
52
0N
EK1
Nim
are
late
dki
nas
e1
(Contin
ued)
WARMAN ET AL. 947
SRPS
type
4(B
eem
er)
AR2
69
86
0O
ral-f
acia
l-dig
ital
syn
drom
ety
pe4
(Moh
r–M
ajew
ski)
AR2
58
86
0
Asph
yxia
tin
gth
orac
icdy
spla
sia
(ATD
;Je
une)
AR2
08
50
03
q25
.33
IFT8
0In
trafl
agel
lar
tran
spor
t8
0(h
omol
ogof
)As
phyx
iati
ng
thor
acic
dysp
lasi
a(A
TD;
Jeun
e)AR
20
85
00
11
q22
.3D
YNC2
H1
Dyn
ein
,cy
top
lasm
ic2
,he
avy
chai
n1
Asph
yxia
tin
gth
orac
icdy
spla
sia
(ATD
;Je
une)
AR2
08
50
0U
nlin
ked
toei
ther
DYN
C2H
1or
IFT8
0Th
orac
olar
yngo
pelv
icdy
spla
sia
(Bar
nes
)AD
18
77
60
See
also
pate
rnal
UPD
14
and
cere
bro-
cost
o-m
andi
bula
rsy
ndro
me
10
.M
ulti
ple
epip
hyse
aldy
spla
sia
and
pseu
doac
hon
drop
lasi
agr
oup
Pseu
doac
hon
drop
lasi
a(P
SACH
)AD
17
71
70
19
p12–
13
.1CO
MP
COM
PM
ulti
ple
epip
hyse
aldy
spla
sia
(MED
)ty
pe1
(ED
M1
)AD
13
24
00
19
p13
.1CO
MP
COM
P
Mul
tipl
eep
iphy
seal
dysp
lasi
a(M
ED)
type
2(E
DM
2)
AD6
00
20
41
p32
.2–
33
COL9
A2Co
llage
n9
alp
ha-
2ch
ain
Mul
tipl
eep
iphy
seal
dysp
lasi
a(M
ED)
type
3(E
DM
3)
AD6
00
96
92
0q1
3.3
COL9
A3Co
llage
n9
alp
ha-
3ch
ain
Mul
tipl
eep
iphy
seal
dysp
lasi
a(M
ED)
type
5(E
DM
5)
AD6
07
07
82
p23–
24
MAT
N3
Mat
rilin
3
Mul
tipl
eep
iphy
seal
dysp
lasi
a(M
ED)
type
6(E
DM
6)
AD1
20
21
06
q13
COL9
A1Co
llage
n9
alp
ha-
1ch
ain
Mul
tipl
eep
iphy
seal
dysp
lasi
a(M
ED),
othe
rty
pes
Som
eM
ED
-like
case
su
nlin
ked
tokn
own
gen
esSt
ickl
ersy
ndr
ome,
rece
ssiv
ety
peAR
12
02
10
6q1
3CO
L9A1
Colla
gen
9al
ph
a-1
chai
nFa
mili
alhi
pdy
spla
sia
(Beu
kes)
AD1
42
66
94
q35
Mul
tipl
eep
iphy
seal
dysp
lasi
aw
ith
mic
roce
phal
yan
dn
ysta
gmus
(Low
ry-W
ood)
AR2
26
96
0
See
also
mul
tipl
eep
iphy
seal
dysp
lasi
a,re
cess
ive
type
(rM
ED;E
DM
4)
insu
lfati
ondi
sord
ers
(gro
up4
),fa
mili
alos
teoc
hond
riti
sdi
ssec
ans
inth
eag
grec
angr
oup,
asw
ella
sAS
PED
inth
eAc
rom
elic
grou
p1
1.
Met
aphy
seal
dysp
lasi
asM
etap
hyse
aldy
spla
sia,
Schm
idty
pe(M
CS)
AD1
56
50
06
q21–
22
.3CO
L10
A1Co
llage
n1
0al
ph
a-1
chai
n
Cart
ilage
-hai
rhy
popl
asia
(CH
H;
met
aphy
seal
dysp
lasi
a,M
cKus
ick
type
)
AR2
50
25
09
p13
RM
RP
RN
Aco
mpo
nen
tof
RN
Ase
HIn
clu
des
anau
xeti
cd
ysp
lasi
a
Met
aphy
seal
dysp
lasi
a,Ja
nse
nty
peAD
15
64
00
3p2
2–
21
.1PT
HR
1PT
H/P
THrP
rece
pto
r1
Acti
vati
ng
mu
tati
ons—
see
also
Blo
mst
ran
dd
ysp
lasi
a(g
rou
p2
2,
23
)Ei
ken
dysp
lasi
aAR
60
00
02
3p2
2–
21
.1PT
HR
1PT
H/P
THrP
rece
pto
r1
Acti
vati
ng
mu
tati
ons—
see
also
Blo
mst
ran
dd
ysp
lasi
a(g
rou
p2
2,
23
)
TAB
LEI(
Con
tin
ued)
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
948 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Met
aphy
seal
dysp
lasi
aw
ith
pan
crea
tic
insu
ffici
ency
and
cycl
icn
eutr
open
ia(S
hwac
hman
–B
odia
n–
Dia
mon
dsy
ndr
ome,
SBD
S)
AR2
60
40
07
q11
SBD
SSB
DS
prot
ein
Met
aphy
seal
anad
yspl
asia
type
1AD
,AR
30
96
45
11
q22
.2M
MP1
3M
atri
xm
etal
lopr
otei
nas
e1
3In
clu
des
SEM
DM
isso
uri
typ
e.B
oth
dom
inan
tan
dre
cess
ive
mu
tati
ons
des
crib
edM
etap
hyse
alan
adys
plas
iaty
pe2
AR2
0q1
3.1
2M
MP9
Mat
rix
met
allo
prot
ein
ase
9M
etap
hyse
aldy
spla
sia,
Spah
rty
peAR
25
04
00
Met
aphy
seal
acro
scyp
hody
spla
sia
(var
ious
type
s)AR
25
02
15
Gen
ocho
ndr
omat
osis
(typ
e1
/typ
e2
)AD
/SP
13
73
60
Met
aphy
seal
chon
drom
atos
isw
ith
D-2
-hyd
roxy
glut
aric
acid
uria
AR/S
PSe
e2
71
55
01
2.
Spon
dylo
met
aph
ysea
ldy
spla
sias
(SM
D)
Spon
dylo
ench
ond
rody
spla
sia
(SPE
NCD
)AR
27
15
50
19
p13
.2AC
P5Ta
rtra
te-r
esis
tan
tac
idph
osp
hat
ase
(TR
AP)
Incl
ud
esco
mb
ined
imm
un
odefi
cien
cyw
ith
auto
imm
un
ity
and
spon
dy
lom
etap
hy
seal
dy
spla
sia
(MIM
60
79
44
)O
don
toch
ondr
odys
plas
ia(O
DCD
)AR
18
42
60
Spon
dylo
met
aphy
seal
dysp
lasi
a,Su
tclif
fety
peor
corn
erfr
actu
res
type
AD1
84
25
5
SMD
wit
hse
vere
gen
uva
lgum
AD1
84
25
3In
clu
des
SMD
Sch
mid
tty
pe
and
SMD
Alge
rian
typ
eSM
Dw
ith
con
e-ro
ddy
stro
phy
AR6
08
94
0SM
Dw
ith
reti
nal
dege
ner
atio
n,
axia
lty
peAR
60
22
71
Dys
spon
dylo
ench
ondr
omat
osis
SPCh
eiro
-spo
ndy
loen
chon
drom
atos
isSP
See
also
grou
p2
9Se
eal
soSM
DK
ozlo
wsk
i(gr
oup
TRPV
4)
diso
rder
sin
grou
p1
1as
wel
las
SMD
Seda
ghat
ian
type
ingr
oup
12
;the
rear
em
any
indi
vidu
alre
port
sof
SMD
vari
ants
13
.Sp
ondy
lo-e
pi-(
met
a)-p
hyse
aldy
spla
sias
(SE(
M)D
)D
yggv
e–M
elch
ior–
Clau
sen
dysp
lasi
a(D
MC)
AR2
23
80
01
8q1
2–
21
.1D
YMD
ymec
linIn
clu
des
Smit
h–
McC
ort
dy
spla
sia
Imm
uno-
osse
ous
dysp
lasi
a(S
chim
ke)
AR2
42
90
02
q34–
36
SMAR
CAL1
SWI/
SNF-
rela
ted
regu
lato
rof
chro
mat
insu
bfa
mily
A-lik
epr
otei
n1
SED
,W
olco
tt–
Ral
lison
type
AR2
26
98
02
p12
EIF2
AK3
Tran
slat
ion
init
iati
onfa
ctor
2-a
lpha
kin
ase-
3SE
MD
,M
atri
linty
peAR
60
87
28
2p2
3–
p24
MAT
N3
Mat
rilin
3Se
eal
som
atri
lin-r
elat
edM
ED
ingr
oup
8SE
MD
,sh
ort
limb—
abn
orm
alca
lcifi
cati
onty
peAR
27
16
65
1q2
3D
DR
2D
isco
idin
dom
ain
rece
pto
rfa
mily
,m
emb
er2
See
also
oth
erd
ysp
lasi
asw
ith
stip
plin
gin
grou
p2
0SE
Dta
rda,
X-lin
ked
(SED
-XL)
XLR
31
34
00
Xp2
2SE
DL
Sedl
inSp
ondy
lo-m
egae
piph
ysea
l-m
etap
hyse
aldy
spla
sia
(SM
MD
)AR
61
33
30
4p1
6.1
NK
X3-2
NK
3H
omeo
box
2
(Contin
ued)
WARMAN ET AL. 949
Spon
dylo
dysp
last
icEh
lers
–D
anlo
ssy
ndr
ome
AR6
12
35
01
1p1
1.2
SLC3
9A1
3Zi
nc
tran
spor
ter
ZIP
13
SPO
NAS
TRIM
Edy
spla
sia
AR2
71
51
0SE
MD
wit
hjo
int
laxi
ty(S
EMD
-JL)
lept
odac
tylic
orH
all
type
AD6
03
54
6
SEM
Dw
ith
join
tla
xity
(SEM
D-J
L)B
eigh
ton
type
AR2
71
64
0
Plat
yspo
ndy
ly(b
rach
yolm
ia)
wit
ham
elog
enes
isim
perf
ecta
AR6
01
21
6
Late
onse
tSE
D,
auto
som
alre
cess
ive
type
AR6
09
22
3
Bra
chyo
lmia
,H
obae
k,an
dTo
ledo
type
sAR
27
15
30
,2
71
63
0N
osol
ogic
rela
tion
ship
bet
wee
nth
eTo
lead
oan
dH
obae
kty
pes
ofb
rach
yol
mia
and
rece
ssiv
ela
te-o
nse
tSE
Dar
eu
ncl
ear,
dis
tin
ctiv
ecr
iter
iala
ckin
gso
far
See
also
Bra
chyo
lmia
(gro
up8
),O
psis
mod
yspl
asia
(gro
up1
4),
SEM
Ds
(gro
up1
1),
muc
opol
ysac
char
idos
isty
pe4
(Mor
quio
synd
rom
e)an
dot
her
cond
itio
nsin
grou
p2
6,
asw
ell
asPP
RD
(SED
wit
hpr
ogre
ssiv
ear
thro
path
y)in
grou
p3
11
4.
Seve
resp
ondy
lody
spla
stic
dysp
lasi
asAc
hon
drog
enes
isty
pe1
A(A
CG1
A)AR
20
06
00
14
q32
.12
TRIP
11
Gol
gi-m
icro
tub
ule
-ass
ocia
ted
prot
ein
,2
10
-kD
a;G
MAP
21
0Sc
hnec
ken
beck
endy
spla
sia
AR2
69
25
01
p31
.3SL
C35
D1
Solu
teca
rrie
rfa
mily
35
mem
ber
D1
;U
DP-
glu
curo
nic
acid
/U
DP-
N-a
cety
lgal
acto
sam
ine
dual
tran
spor
ter
Spon
dylo
met
aphy
seal
dysp
lasi
a,Se
dagh
atia
nty
peAR
25
02
20
Seve
resp
ondy
lom
etap
hyse
aldy
spla
sia
(SM
DSe
dagh
atia
n-l
ike)
AR7
q11
SBD
SSB
DS
gen
e,fu
nct
ion
still
uncl
ear
Ops
ism
odys
plas
iaAR
25
84
80
See
also
Than
atop
hori
cdy
spla
sia,
type
s1
and
2(g
roup
1);
ACG
2an
dTo
rran
cedy
spla
sia
(gro
up2
);Fi
broc
hond
roge
nesi
s(g
roup
3);
Acho
ndro
gene
sis
type
1B
(ACG
1B
,gro
up4
);an
dM
etat
ropi
cdy
spla
sia
(TR
PV4
grou
p)1
5.
Acro
mel
icdy
spla
sias
Tric
horh
inop
hala
nge
aldy
spla
sia
type
s1
/3AD
19
03
50
8q2
4TR
PS1
Zin
cfi
nge
rtr
ansc
ript
ion
fact
orTr
icho
rhin
opha
lan
geal
dysp
lasi
aty
pe2
(Lan
ger–
Gie
dion
)AD
15
02
30
8q2
4TR
PS1
and
EXT1
Zin
cfi
nge
rtr
ansc
rip
tion
fact
oran
dE
xost
osin
1M
icro
del
etio
nsy
nd
rom
e;se
eal
soM
ult
iple
Cart
ilagi
neo
us
Exo
stos
esin
grou
p2
8Ac
roca
pito
fem
oral
dysp
lasi
aAR
60
77
78
2q3
3–
q35
IHH
Indi
anhe
dgeh
ogCr
anio
ecto
derm
aldy
spla
sia
(Lev
in–
Sen
sen
bren
ner
)ty
pe1
AR2
18
33
03
q21
IFT1
22
Intr
aflag
ella
rtr
ansp
ort
12
2(C
hlam
yd
omon
as,
hom
olog
of)
Cran
ioec
tode
rmal
dysp
lasi
a(L
evin
–Se
nse
nbr
enn
er)
type
2AR
61
36
10
2p2
4.1
WD
R3
5W
Dre
peat
-con
tain
ing
prot
ein
35
TAB
LEI(
Con
tin
ued)
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
950 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Gel
eoph
ysic
dysp
lasi
aAR
23
10
50
9q3
4.2
ADAM
TSL2
ADAM
TS-li
kep
rote
in2
Gel
eoph
ysic
dysp
lasi
a,ot
her
type
sAR
Un
linke
dto
ADAM
TSL2
Acro
mic
ric
dysp
lasi
aAD
10
23
70
Incl
ud
esac
rola
ryn
geal
dy
spla
sia,
pre
viou
sly
know
nas
Fan
tasy
Isla
nd
dy
spla
sia
orTa
ttoo
dy
spla
sia
Acro
dyso
stos
isAD
10
18
00
Ange
l-sha
ped
phal
ango
-epi
phys
eal
dysp
lasi
a(A
SPED
)AD
10
58
35
Pos
sib
lyre
late
dor
alle
licto
Bra
chy
dac
tyly
typ
eC
Sald
ino–
Mai
nze
rdy
spla
sia
AR2
66
92
0Se
eal
sosh
ort
rib
dysp
lasi
asgr
oup
16
.Ac
rom
esom
elic
dysp
lasi
asAc
rom
esom
elic
dysp
lasi
aty
peM
arot
eaux
(AM
DM
)AR
60
28
75
9p1
3–
12
NPR
2N
atri
uret
icp
epti
de
rece
ptor
2G
rebe
dysp
lasi
aAR
20
07
00
20
q11
.2G
DF5
Gro
wth
and
diff
eren
tiat
ion
fact
or5
Incl
ud
esac
rom
esom
elic
dy
spla
sia
Hu
nte
r-Th
omp
son
typ
e;se
eal
soB
rach
yd
acty
lies
(gro
up
34
)Fi
bula
rhy
popl
asia
and
com
plex
brac
hyda
ctyl
y(D
uPa
n)
AR2
28
90
02
0q1
1.2
GD
F5G
row
than
dd
iffer
enti
atio
nfa
ctor
5Se
eal
soB
rach
yd
acty
lies
(gro
up
34
)Ac
rom
esom
elic
dysp
lasi
aw
ith
gen
ital
anom
alie
sAR
60
94
41
4q2
3–
24
BM
PR1
BB
one
mor
phog
enet
icpr
otei
nre
cep
tor
1B
Acro
mes
omel
icdy
spla
sia,
Ose
bold
-Rem
ondi
ni
type
AD1
12
91
0
17
.M
esom
elic
and
rhiz
o-m
esom
elic
dysp
lasi
asD
ysch
ondr
oste
osis
(Ler
i–W
eill)
Pseu
do-A
D1
27
30
0Xp
ter-
p22
.32
SHO
XSh
ort
stat
ure—
hom
eob
oxge
ne
Incl
ud
esR
ein
har
dt–
Pfe
iffer
dy
spla
sia,
MIM
19
14
00
Lan
ger
type
(hom
ozyg
ous
dysc
hon
dros
teos
is)
Pseu
do-A
R2
49
70
0Xp
ter-
p22
.32
SHO
XSh
ort
stat
ure—
hom
eob
oxge
ne
Om
odys
plas
iaAR
25
83
15
13
q31–
q32
GPC
6G
lypi
can
6E
xist
ence
of‘‘d
omin
ant
omod
ysp
lasi
a’’(
MIM
16
47
45
)re
mai
ns
tob
eco
nfi
rmed
Rob
inow
syn
drom
e,re
cess
ive
type
AR2
68
31
09
q22
RO
R2
Rec
epto
rty
rosi
ne
kin
ase-
like
orph
anre
cep
tor
2In
clu
des
pre
viou
sco
sto-
vert
ebra
lseg
men
tati
ond
efec
tw
ith
mes
omel
ia(C
OVE
SDE
M);
see
also
bra
chy
dac
tyly
typ
eB
Rob
inow
syn
drom
e,do
min
ant
type
AD1
80
70
0M
esom
elic
dysp
lasi
a,K
orea
nty
peAD
2q2
4–
32
Dup
licat
ion
inH
OXD
gen
ecl
ust
erM
esom
elic
dysp
lasi
a,K
anta
putr
aty
peAD
15
62
32
2q2
4–
32
Dup
licat
ion
sin
HO
XDge
ne
clu
ster
Mes
omel
icdy
spla
sia,
Nie
verg
elt
type
AD1
63
40
0M
esom
elic
dysp
lasi
a,K
ozlo
wsk
i-Rea
rdon
type
AR2
49
71
0
Mes
omel
icdy
spla
sia
wit
hac
ral
syn
osto
ses
(Ver
loes
–D
avid
–Pf
eiff
erty
pe)
AD6
00
38
38
q13
SULF
1an
dSL
CO5
A1H
epar
ansu
lfate
6-O
-en
dosu
lfata
se1
and
solu
teca
rrie
ror
gan
ican
ion
tran
s-po
rter
fam
ilym
emb
er5
A1
Mic
rod
elet
ion
syn
dro
me
invo
lvin
gtw
oad
jace
nt
gen
es
(Contin
ued)
WARMAN ET AL. 951
Mes
omel
icdy
spla
sia,
Sava
rira
yan
type
(Tri
angu
lar
Tibi
a–Fi
bula
rAp
lasi
a)SP
60
52
74
Pos
sib
lyre
late
dto
Nie
verg
elt
dy
spla
sia.
On
eca
sere
por
ted
wit
h2
q1
1.2
mic
rod
elet
ion
ofu
ncl
ear
sign
ifica
nce
18
.B
ent
bon
esdy
spla
sias
Cam
pom
elic
dysp
lasi
a(C
D)
AD1
14
29
01
7q2
4.3
–2
5.1
SOX9
SRY-
box
9In
clu
des
acam
pom
elic
cam
pom
elic
dy
spla
sia
(ACD
)as
wel
las
mild
cam
pom
elic
dy
spla
sia
(MIM
60
21
96
)St€ uv
e–W
iede
man
ndy
spla
sia
AR6
01
55
95
p13
.1LI
FRLe
ukem
iain
hib
itor
yfa
ctor
rece
pto
rIn
clu
des
form
erly
neo
nat
alSc
hw
artz
–Ja
mp
elsy
nd
rom
eor
SJS
typ
e2
Kyp
hom
elic
dysp
lasi
a,se
vera
lfo
rms
21
13
50
Pro
bab
lyh
eter
ogen
eou
sB
ent
bone
sat
birt
hca
nbe
seen
ina
vari
ety
ofco
ndit
ions
,in
clud
ing
oste
ogen
esis
impe
rfec
ta,
Antl
ey–
Bix
ler
synd
rom
e,ca
rtila
ge-h
air
hypo
plas
ia,
Cum
min
gssy
ndro
me,
hypo
phos
phat
asia
,dy
sseg
men
tal
dysp
lasi
a,TD
,ATD
,and
othe
rs1
9.
Slen
der
bon
edy
spla
sia
grou
p3
-Msy
ndr
ome
(3M
1)
AR2
73
75
06
p21
.1CU
L7Cu
llin
7In
clu
des
dol
ich
osp
ond
ylic
dy
spla
sia
and
Yaku
tsh
ort
stat
ure
syn
dro
me
3-M
syn
drom
e(3
M2
)AR
61
29
21
2q3
5O
BSL
1O
bscu
rin
-like
1K
enn
y–
Caff
eydy
spla
sia
type
1AR
24
44
60
1q4
2–
q43
TBCE
Tubu
lin-s
peci
fic
chap
eron
eE
Ken
ny–
Caff
eydy
spla
sia
type
2AD
12
70
00
Mic
roce
phal
icos
teod
yspl
asti
cpr
imor
dial
dwar
fism
type
1/3
(MO
PD1
)AR
21
07
10
2q
Incl
ud
esTa
yb
i–Li
nd
erce
ph
alos
kele
tal
dy
spla
sia
Mic
roce
phal
icos
teod
yspl
asti
cpr
imor
dial
dwar
fism
type
2(M
OPD
2;
Maj
ewsk
ity
pe)
AR2
10
72
02
1q
PCN
T2Pe
rice
ntr
in2
IMAG
Esy
ndr
ome
(in
trau
teri
ne
grow
thre
tard
atio
n,
met
aphy
seal
dysp
lasi
a,ad
ren
alhy
popl
asia
,an
dge
nit
alan
omal
ies)
XL/A
D3
00
29
0P
ossi
bly
het
erog
eneo
us
Ost
eocr
anio
sten
osis
SP6
02
36
1O
ccu
rren
cein
sib
sre
por
ted
,in
her
itan
ceu
ncl
ear
Hal
lerm
ann–
Stre
iffsy
ndr
ome
AR2
34
10
0M
uta
tion
sin
GJA
1re
por
ted
inon
eca
seon
lySe
eal
soCe
rebr
o-ar
thro
-dig
ital
dysp
lasi
a2
0.
Dys
plas
ias
wit
hm
ulti
ple
join
tdi
sloc
atio
ns
Des
buqu
ois
dysp
lasi
a(w
ith
acce
ssor
yos
sifi
cati
once
nte
rin
digi
t2
)AR
25
14
50
17
q25
.3CA
NT1
Des
buqu
ois
dysp
lasi
aw
ith
shor
tm
etac
arpa
lsan
del
onga
ted
phal
ange
s(K
imty
pe)
AR2
51
45
01
7q2
5.3
CAN
T1
TAB
LEI(
Con
tin
ued)
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
952 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Des
buqu
ois
dysp
lasi
a(o
ther
vari
ants
wit
hor
wit
hout
acce
ssor
yos
sifi
cati
once
nte
r)
ARP
rob
ably
gen
etic
ally
het
erog
eneo
us
Pseu
dodi
astr
oph
icdy
spla
sia
AR2
64
18
0Se
eal
soSE
Dw
ith
cong
enit
aldi
sloc
atio
ns,
CHST
3ty
pe(g
roup
4);
Atel
oste
ogen
esis
type
3an
dLa
rsen
synd
rom
e(g
roup
6);
SEM
Ds
wit
hjo
int
laxi
ty(g
roup
11
)2
1.
Chon
drod
yspl
asia
pun
ctat
a(C
DP)
grou
pCD
P,X-
linke
ddo
min
ant,
Con
radi
–H€ un
erm
ann
type
(CD
PX2
)XL
D3
02
96
0Xp
11
EBP
Emop
amil-
bin
din
gp
rote
in
CDP,
X-lin
ked
rece
ssiv
e,br
achy
tele
phal
angi
cty
pe(C
DPX
1)
XLR
30
29
50
Xp2
2.3
ARSE
Aryl
sulfa
tase
E
Con
gen
ital
hem
idys
plas
ia,
icht
hyos
is,
limb
defe
cts
(CH
ILD
)XL
D3
08
05
0Xp
11
NSD
HL
NAD
(P)H
ster
oid
dehy
drog
enas
e-lik
ep
rote
inCo
nge
nit
alhe
mid
yspl
asia
,ic
hthy
osis
,lim
bde
fect
s(C
HIL
D)
XLD
30
80
50
Xq2
8EB
PEm
opam
il-bi
nd
ing
pro
tein
Gre
enbe
rgdy
spla
sia
AR2
15
14
01
q42
.1LB
RLa
min
Bre
cep
tor,
3-b
eta-
hyd
roxy
ster
old
elta
(14
)-re
duct
ase
Incl
ud
esh
yd
rop
s-ec
top
icca
lcifi
cati
on-m
oth
-eat
enap
pea
ran
ced
ysp
lasi
a(H
EM
)an
dd
app
led
dia
ph
yse
ald
ysp
lasi
aR
hizo
mel
icCD
Pty
pe1
AR2
15
10
06
q22–
24
PEX7
Pero
xiso
mal
PTS
2re
cep
tor
Rhi
zom
elic
CDP
type
2AR
22
27
65
1q4
2D
HPA
TD
ihyd
roxy
acet
onep
hos
ph
ate
acyl
tran
sfer
ase
(DH
APAT
)R
hizo
mel
icCD
Pty
pe3
AR6
00
12
12
q31
AGPS
Alky
lgly
cero
ne-
ph
osp
hat
esy
nth
ase
(AG
PS)
CDP
tibi
al-m
etac
arpa
lty
peAD
/AR
11
86
51
Nos
olog
icst
atu
su
nce
rtai
nAs
tley
-Ken
dall
dysp
lasi
aAR
?R
elat
ion
ship
toO
Ian
dto
Gre
enb
erg
dy
spla
sia
un
clea
rN
ote
that
stip
plin
gca
noc
curi
nse
vera
lsyn
drom
essu
chas
Zellw
eger
,Sm
ith–
Lem
li–O
pitz
and
othe
rs.S
eeal
sode
smos
tero
losi
sas
wel
las
SEM
Dsh
ortl
imb—
abno
rmal
calc
ifica
tion
type
ingr
oup
11
22
.N
eon
atal
oste
oscl
erot
icdy
spla
sias
Blo
mst
ran
ddy
spla
sia
AR2
15
04
53
p22–
21
.1PT
HR
1PT
H/P
THrP
rece
pto
r1
Cau
sed
by
rece
ssiv
ein
acti
vati
ng
mu
tati
ons;
see
also
Eik
end
ysp
lasi
aan
dJa
nse
nd
ysp
lasi
aD
esm
oste
rolo
sis
AR6
02
39
81
p33–
31
.1D
HCR
24
3-b
eta-
hydr
oxy
ster
olde
lta-
24
-red
uct
ase
See
also
oth
erst
erol
-m
etab
olis
mre
late
dco
nd
itio
ns
Caff
eydi
seas
e(i
ncl
udin
gin
fan
tile
and
atte
nua
ted
form
s)AD
11
40
00
17
q21–
22
COL1
A1Co
llage
n1
,al
ph
a-1
chai
nSe
eal
soos
teog
enes
isim
per
fect
are
late
dto
colla
gen
1ge
nes
(gro
up
24
)Ca
ffey
dise
ase
(sev
ere
vari
ants
wit
hpr
enat
alon
set)
AR1
14
00
0
Rai
ne
dysp
lasi
a(l
etha
lan
dn
on-le
thal
form
s)AR
25
97
75
7p2
2FA
M2
0C
Incl
ud
esle
thal
and
non
-leth
alca
ses
See
also
Astl
ey-K
end
alld
yspl
asia
and
CDPs
ingr
oup
21
23
.In
crea
sed
bon
ede
nsi
tygr
oup
(wit
hout
mod
ifica
tion
ofbo
ne
shap
e)O
steo
petr
osis
,se
vere
neo
nat
alor
infa
nti
lefo
rms
(OPT
B1
)AR
25
97
00
11
q13
TCIR
G1
Subu
nit
ofAT
Pas
ep
roto
npu
mp
Ost
eope
tros
is,
seve
ren
eon
atal
orin
fan
tile
form
s(O
PTB
4)
AR6
11
49
01
6p1
3CL
CN7
Chlo
ride
chan
nel
7
( Contin
ued)
WARMAN ET AL. 953
Ost
eope
tros
is,
infa
nti
lefo
rm,
wit
hn
ervo
ussy
stem
invo
lvem
ent
(OPT
B5
)AR
25
97
20
6q2
1O
STM
1G
ray
leth
al/o
steo
pet
rosi
sas
soci
ated
tran
smem
bra
ne
prot
ein
Ost
eope
tros
is,
inte
rmed
iate
form
,os
teoc
last
-poo
r(O
PTB
2)
AR2
59
71
01
3q1
4.1
1R
ANK
L(T
NFS
F11
)R
ecep
tor
acti
vato
rof
NF-
kap
pa-
Blig
and
(tum
orn
ecro
sis
fact
orli
gan
dsu
perf
amily
,mem
ber
11
)O
steo
petr
osis
,in
fan
tile
form
,os
teoc
last
-poo
rw
ith
imm
unog
lobu
linde
fici
ency
(OPT
B7
)
AR6
12
30
21
8q2
1.3
3R
ANK
(TN
FRSF
11
A)R
ecep
tor
acti
vato
rof
NF-
kapp
a-B
See
also
fam
ilial
exp
ansi
leos
teol
ysi
sin
Ost
eoly
sis
grou
p(g
rou
p2
8)
Ost
eope
tros
is,
inte
rmed
iate
form
(OPT
B6
)AR
61
14
97
17
q21
.3PL
EKH
M1
Plec
kstr
inho
mol
ogy
dom
ain
-con
tain
ing
pro
tein
,fa
mily
M,
mem
ber
1O
steo
petr
osis
,in
term
edia
tefo
rm(O
PTA2
)AR
25
97
10
16
p13
CLCN
7Ch
lori
dech
ann
elp
um
p
Ost
eope
tros
isw
ith
ren
altu
bula
rac
idos
is(O
PTB
3)
AR2
59
73
08
q22
CA2
Carb
onic
anh
yd
rase
2
Ost
eope
tros
is,
late
-on
set
form
type
1(O
PTA1
)AD
60
76
34
11
q13
.4LR
P5Lo
wde
nsi
tylip
opro
tein
rece
ptor
-rel
ated
pro
tein
5In
clu
des
Wor
thty
pe
oste
oscl
eros
is(M
IM1
44
75
0)
Ost
eope
tros
is,
late
-on
set
form
type
2(O
PTA2
)AD
16
66
00
16
p13
CLCN
7Ch
lori
dech
ann
el7
Ost
eope
tros
isw
ith
ecto
derm
aldy
spla
sia
and
imm
une
defe
ct(O
LED
AID
)XL
30
03
01
Xq2
8IK
BK
G(N
EMO
)In
hibi
tor
ofka
pp
alig
ht
poly
pept
ide
gen
een
han
cer,
kin
ase
ofO
steo
petr
osis
,m
oder
ate
form
wit
hde
fect
ive
leuc
ocyt
ead
hesi
on(L
AD3
)AR
61
28
40
11
q12
FER
MT3
(KIN
D3
)Fe
rmit
in3
(Kin
dlin
3)
Ost
eope
tros
is,
mod
erat
efo
rmw
ith
defe
ctiv
ele
ucoc
yte
adhe
sion
AR6
12
84
01
1q1
3R
ASG
RP2
(Cal
DAG
-GEF
1)
Ras
guan
yln
ucl
eoti
de-
rele
asin
gp
rote
in2
Pykn
odys
osto
sis
AR2
65
80
01
q21
CTSK
Cath
epsi
nK
Ost
eopo
ikilo
sis
AD1
55
95
01
2q1
4LE
MD
3LE
Mdo
mai
n-c
onta
inin
g3
Incl
ud
esB
usc
hke
–O
llen
dor
ffsy
nd
rom
e(M
IM1
66
70
0)
Mel
orhe
osto
sis
wit
hos
teop
oiki
losi
sAD
15
59
50
12
q14
LEM
D3
LEM
dom
ain
-con
tain
ing
3In
clu
des
mix
edsc
lero
sin
gb
one
dy
spla
sia
Ost
eopa
thia
stri
ata
wit
hcr
ania
lsc
lero
sis
(OSC
S)XL
D3
00
37
3Xq
11
.1W
TXFA
M1
23
B
Mel
orhe
osto
sis
SPN
oge
rmlin
eLE
MD
3m
uta
tion
sid
enti
fied
sofa
rD
ysos
teos
cler
osis
AR2
24
30
0P
ossi
bly
rela
ted
to‘‘o
steo
scle
roti
cm
etap
hy
seal
dy
spla
sia’
’O
steo
mes
opyk
nos
isAD
16
64
50
Ost
eope
tros
isw
ith
infa
nti
len
euro
axon
aldy
spla
sia
AR?
60
03
29
Sam
eas
oste
opet
rosi
sw
ith
ner
vou
ssy
stem
invo
lvem
ent
(see
abov
e)?
TAB
LEI(
Con
tin
ued
)
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
954 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
24
.In
crea
sed
bon
ede
nsi
tygr
oup
wit
hm
etap
hyse
al
and/
ordi
aphy
seal
invo
lvem
ent
Cran
iom
etap
hyse
aldy
spla
sia,
auto
som
aldo
min
ant
type
AD1
23
00
05
p15
.2–
14
.2AN
KH
Hom
olog
ofm
ouse
ANK
(an
kylo
sis)
gen
eG
ain
offu
nct
ion
mu
tati
ons
Dia
phys
eal
dysp
lasi
aCa
mur
ati-E
nge
lman
nAD
13
13
00
19
q13
TGFb
eta1
Tran
sfor
min
ggr
owth
fact
orbe
ta1
Hem
atod
iaph
ysea
ldy
spla
sia
Gho
sal
AR2
31
09
57
q34
TBXA
S1Th
rom
boxa
ne
Asy
nth
ase
1H
yper
trop
hic
oste
oart
hrop
athy
AR2
59
10
04
q34–
35
HPG
D1
5-a
lpha
-hy
drox
ypro
stag
lan
din
dehy
drog
enas
e
Incl
udes
cran
io-o
steo
arth
ropa
thy
and
case
sof
rece
ssiv
ep
ach
yd
erm
oper
iost
osis
Pach
yder
mop
erio
stos
is(h
yper
trop
hic
oste
oart
hrop
ath
y,pr
imar
y,au
toso
mal
dom
inan
t)
AD1
67
10
0R
elat
ion
ship
tore
cess
ive
form
(MIM
25
91
00
,H
PG
Dd
efici
ency
)u
ncl
ear
Ocu
lode
nto
osse
ous
dysp
lasi
a(O
DO
D)
mild
type
AD1
64
20
06
q22–
23
GJA
1G
apju
nct
ion
pro
tein
alph
a-1
Ocu
lode
nto
osse
ous
dysp
lasi
a(O
DO
D)
seve
rety
peAR
25
78
50
Pos
sib
lyh
omoz
ygo
us
form
ofm
ildO
DO
DO
steo
ecta
sia
wit
hhy
perp
hosp
hata
sia
(juv
enile
Page
tdi
seas
e)AR
23
90
00
8q2
4O
PGO
steo
prot
eger
in
Scle
rost
eosi
sAR
26
95
00
17
q12–
21
SOST
Scle
rost
inEn
dost
eal
hype
rost
osis
,va
nB
uche
mty
peAR
23
91
00
17
q12–
21
SOST
Scle
rost
inSp
ecifi
c5
2kb
del
etio
nd
own
stre
amof
SOST
Tric
hode
nto
osse
ous
dysp
lasi
aAD
19
03
20
17
q21
DLX
3D
ista
l-les
sh
omeo
box
3Cr
anio
met
aphy
seal
dysp
lasi
a,au
toso
mal
rece
ssiv
ety
peAR
21
84
00
6q2
1–
22
Dia
phys
eal
med
ulla
ryst
enos
isw
ith
bon
em
alig
nan
cyAD
11
22
50
9p2
1–
p22
Cran
iodi
aphy
seal
dysp
lasi
aAD
12
28
60
Cran
iom
etad
iap
hyse
aldy
spla
sia,
Wor
mia
nbo
ne
type
AR—
Endo
stea
lsc
lero
sis
wit
hce
rebe
llar
hypo
plas
iaAR
21
30
02
Len
z–M
ajew
ski
hype
rost
otic
dysp
lasi
aSP
15
10
50
Met
aphy
seal
dysp
lasi
a,B
raun
–Ti
nsc
hert
type
XL6
05
94
6
Pyle
dise
ase
AR2
65
90
02
5.
Ost
eoge
nes
isim
perf
ecta
and
decr
ease
dbo
ne
den
sity
grou
pFo
rco
mm
ents
the
clas
sific
atio
nof
oste
ogen
esis
impe
rfec
ta,
plea
sere
fer
toth
ete
xtO
steo
gen
esis
impe
rfec
ta,
non
-def
orm
ing
form
(OI
type
1)
ADCO
L1A1
,CO
L1A2
COL1
A1:
colla
gen
1al
pha-
1ch
ain
,CO
L1A2
:co
llage
n1
alp
ha-
2ch
ain
,CR
TAP:
cart
ilage
-ass
ocia
ted
prot
ein
,LE
PR
E1
:le
uci
ne
prol
ine-
enri
ched
pro
teog
lyca
n(l
epre
can
)1
,PP
IB:p
epti
dy
lpro
lyl
isom
eras
eB
(cy
clop
hili
nB
),FK
BP1
0:
FK5
06
bin
din
gp
rote
in1
0,
SER
PIN
H:
serp
inp
epti
das
ein
hibi
tor
clad
eH
1,
SP7
:SP
7tr
ansc
ript
ion
fact
or(O
ster
ix)
Ost
eoge
nes
isim
perf
ecta
,pe
rin
atal
leth
alfo
rm(O
Ity
pe2
)AD
,AR
COL1
A1,
COL1
A2,
CRTA
P,LE
PRE1
,PPI
BO
steo
gen
esis
impe
rfec
ta,
prog
ress
ivel
yde
form
ing
type
(OI
type
3)
AD,
ARCO
L1A1
,CO
L1A2
,CR
TAP,
LEPR
E1,
PPIB
,FK
BP1
0,
SER
PIN
H1
See
also
Bru
cksy
nd
rom
ety
pe
1(b
elow
)
Ost
eoge
nes
isim
perf
ecta
,m
oder
ate
form
(OI
type
4)
AD,
ARCO
L1A1
,CO
L1A2
,CR
TAP,
FKB
P10
,SP
7
(Contin
ued)
WARMAN ET AL. 955
Ost
eoge
nes
isim
perf
ecta
wit
hca
lcifi
cati
onof
the
inte
ross
eou
sm
embr
anes
and/
orhy
pert
roph
icca
llus
(OI
type
5)
AD6
10
96
7
Ost
eoge
nes
isim
perf
ecta
,ot
her
type
sB
ruck
syn
drom
ety
pe1
(BS1
)AR
25
94
50
17
q21
FKB
P10
FK5
06
bin
din
gp
rote
in1
0Se
eau
toso
mal
rece
ssiv
eO
I,ab
ove;
intr
afam
ilial
vari
abili
tyb
etw
een
OI3
and
BS1
doc
um
ente
dB
ruck
syn
drom
ety
pe2
(BS2
)AR
60
92
20
3q2
3–
24
PLO
D2
Proc
olla
gen
lysy
lhy
drox
ylas
e2
Ost
eopo
rosi
s-ps
eudo
glio
ma
syn
drom
eAR
25
97
70
11
q12–
13
LRP5
LDL-
rece
ptor
rela
ted
prot
ein
5Ca
lvar
ial
doug
hnut
lesi
ons
wit
hbo
ne
frag
ility
AD1
26
55
0
Idio
path
icju
ven
ileos
teop
oros
isSP
25
97
50
Som
ep
atie
nts
rep
orte
dw
ith
het
eroz
ygo
us
mu
tati
ons
inth
eLR
P5ge
ne
Cole
-Car
pen
ter
dysp
lasi
a(b
one
frag
ility
wit
hcr
anio
syn
osto
sis)
SP1
12
24
0Se
eal
socr
anio
syn
osto
sis
syn
dro
mes
ingr
oup
30
Spon
dylo
-ocu
lar
dysp
lasi
aAR
60
58
22
Un
linke
dto
colla
gen
1an
dco
llage
n2
gen
esor
LRP5
Ost
eope
nia
wit
hra
diol
ucen
tle
sion
sof
the
man
dibl
eAD
16
62
60
Ehle
rs–
Dan
los
syn
drom
e,pr
oger
oid
form
AR1
30
07
05
q35
B4
GAL
T7Xy
losy
lpro
tein
4-b
eta-
gala
ctos
yltr
ansf
eras
ede
fici
ency
Ger
oder
ma
oste
odys
plas
ticu
mAR
23
10
70
1q2
4.2
GO
RAB
SCYL
1-b
ind
ing
pro
tein
1Cu
tis
laxa
,au
toso
mal
rece
ssiv
efo
rm,
type
2B
(AR
CL2
B)
AR6
12
94
01
7q2
5.3
PYCR
1Py
rrol
ine-
5-c
arb
oxy
late
redu
ctas
e1
Skel
etal
feat
ure
sov
erla
pp
ing
wit
hp
roge
roid
ED
San
dge
rod
erm
aos
teod
ysp
last
icu
mCu
tis
laxa
,au
toso
mal
rece
ssiv
efo
rm,
type
2A
(AR
CL2
A)(W
rin
kly
skin
syn
drom
e)
AR2
78
25
0,
21
92
00
12
q24
.3AT
P6VO
A2AT
Pase
,Hþ
tran
spor
tin
g,ly
soso
mal
,V0
sub
un
itA2
Skel
etal
feat
ure
sov
erla
pp
ing
wit
hp
roge
roid
ED
San
dge
rod
erm
aos
teod
ysp
last
icu
mSi
ngl
eton
–M
erte
ndy
spla
sia
AD1
82
25
02
6.
Abn
orm
alm
iner
aliz
atio
ngr
oup
Hyp
opho
spha
tasi
a,pe
rin
atal
leth
alan
din
fan
tile
form
sAR
24
15
00
1p3
6.1
–p3
4AL
PLAl
kalin
eph
osp
hat
ase,
tiss
uen
on-s
pec
ific
(TN
SALP
)
Intr
afam
ilial
vari
abili
ty
Hyp
opho
spha
tasi
a,ad
ult
form
AD1
46
30
01
p36
.1–
p34
ALPL
Alka
line
phos
ph
atas
e,ti
ssue
non
-sp
ecifi
c(T
NSA
LP)
Incl
ud
esod
onto
hy
pop
hos
ph
atas
ia
TAB
LEI(
Con
tin
ued
)
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
956 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Hyp
opho
spha
tem
icri
cket
s,X-
linke
ddo
min
ant
XLD
30
78
00
Xp2
2PH
EXX-
linke
dhy
pop
hos
ph
atem
iam
embr
ane
pro
teas
eH
ypop
hosp
hate
mic
rick
ets,
auto
som
aldo
min
ant
AD1
93
10
01
2p1
3.3
FGF2
3Fi
brob
last
grow
thfa
ctor
23
Hyp
opho
spha
tem
icri
cket
s,au
toso
mal
rece
ssiv
e,ty
pe1
(AR
HR
1)
AR2
41
52
04
q21
DM
P1D
enti
nm
atri
xac
idic
phos
phop
rote
in1
Hyp
opho
spha
tem
icri
cket
s,au
toso
mal
rece
ssiv
e,ty
pe2
(AR
HR
2)
AR6
13
31
26
q23
ENPP
1Ec
ton
ucle
otid
epy
roph
osp
hat
ase/
phos
phod
iest
eras
e1
Hyp
opho
spha
tem
icri
cket
sw
ith
hype
rcal
ciur
ia,
X-lin
ked
rece
ssiv
eXL
R3
00
55
4Xp
11
.22
ClCN
5Ch
lori
dech
ann
el5
Par
tof
Den
t’sd
isea
seco
mp
lex
Hyp
opho
spha
tem
icri
cket
sw
ith
hype
rcal
ciur
ia,
auto
som
alre
cess
ive
(HH
RH
)
AR2
41
53
99
q34
SLC3
4A3
Sodi
um-p
hosp
hat
eco
tran
spor
ter
Neo
nat
alhy
perp
arat
hyro
idis
m,
seve
refo
rmAR
23
92
00
3q1
3
