Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations.
A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.
Johnston
Jennifer J
JJ
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4472, USA. jjohnsto@mail.nih.gov
Sapp
Julie C
JC
Turner
Joyce T
JT
Amor
David
D
Aftimos
Salim
S
Aleck
Kyrieckos A
KA
Bocian
Maureen
M
Bodurtha
Joann N
JN
Cox
Gerald F
GF
Curry
Cynthia J
CJ
Day
Ruth
R
Donnai
Dian
D
Field
Michael
M
Fujiwara
Ikuma
I
Gabbett
Michael
M
Gal
Moran
M
Graham
John M
JM
Hedera
Peter
P
Hennekam
Raoul C M
RC
Hersh
Joseph H
JH
Hopkin
Robert J
RJ
Kayserili
Hülya
H
Kidd
Alexa M J
AM
Kimonis
Virginia
V
Lin
Angela E
AE
Lynch
Sally Ann
SA
Maisenbacher
Melissa
M
Mansour
Sahar
S
McGaughran
Julie
J
Mehta
Lakshmi
L
Murphy
Helen
H
Raygada
Margarita
M
Robin
Nathaniel H
NH
Rope
Alan F
AF
Rosenbaum
Kenneth N
KN
Schaefer
G Bradley
GB
Shealy
Amy
A
Smith
Wendy
W
Soller
Maria
M
Sommer
Annmarie
A
Stalker
Heather J
HJ
Steiner
Bernhard
B
Stephan
Mark J
MJ
Tilstra
David
D
Tomkins
Susan
S
Trapane
Pamela
P
Tsai
Anne Chun-Hui
AC
Van Allen
Margot I
MI
Vasudevan
Pradeep C
PC
Zabel
Bernhard
B
Zunich
Janice
J
Black
Graeme C M
GC
Biesecker
Leslie G
LG
D000015:Abnormalities, Multiple / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics; D005838:Genotype; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D009056:Mouth Abnormalities / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D054975:Pallister-Hall Syndrome / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics / Q000473:pathology*; D013576:Syndactyly / Q000235:genetics / Q000473:pathology*; D000074290:Zinc Finger Protein Gli3
C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3