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780
LETTER TO JMG
Mutations in PHF8 are associated with X linked mental
retardation and cleft lip/cleft palate
F Laumonnier*, S Holbert*, N Ronce, F Faravelli, S Lenzner, C E Schwartz, J Lespinasse, H Van
Esch, D Lacombe, C Goizet, F Phan-Dinh Tuy, H van Bokhoven, J-P Fryns, J Chelly, H-H Ropers,
C Moraine, B C J Hamel, S Briault
...............................................................................................................................
J Med Genet 2005;42:780–786. doi: 10.1136/jmg.2004.029439
Truncating mutations were found in the PHF8 gene (encoding
the PHD finger protein 8) in two unrelated families with X
linked mental retardation (XLMR) associated with cleft lip/
palate (MIM 300263). Expression studies showed that this
gene is ubiquitously transcribed, with strong expression of
the mouse orthologue Phf8 in embryonic and adult brain
structures. The coded PHF8 protein harbours two functional
domains, a PHD finger and a JmjC (Jumonji-like C terminus)
domain, implicating it in transcriptional regulation and
chromatin remodelling. The association of XLMR and cleft
lip/palate in these patients with mutations in PHF8 suggests
an important function of PHF8 in midline formation and in the
development of cognitive abilities, and links this gene to
XLMR associated with cleft lip/palate. Further studies will
explore the specific mechanisms whereby PHF8 alterations
lead to mental retardation and midline defects.
X
linked mental retardation (XLMR) is an inherited
condition that causes failure to develop cognitive
abilities because of mutations in several genes on the
X chromosome. XLMR is a highly heterogeneous condition
affecting around 1.6/1000 males, with a carrier frequency of
2.4/1000 females.1 2 More than 200 XLMR conditions have
been described,3 which can be divided as follows:
N
N
non-syndromic forms (MRX), in which mental retardation
is the only clinical manifestation; 81 MRX families have
been reported so far;
syndromic forms (MRXS), in which mental retardation is
associated with biochemical abnormalities, neurological
features, or recognisable physical signs such as skeletal
abnormalities or facial dysmorphy.3 4
Both MRX and MRXS genes have been located at various
regions on the X chromosome. To date, more than 40 genes
responsible for MRXS and 24 genes responsible for MRX have
been cloned.3 5 Furthermore, it has been shown that
mutations in a single gene—such as ARX,6 7 MECP2,8 9 or
RSK210—could lead to a wide spectrum of clinical features
that encompass both MRX and MRXS conditions. Based on
the distribution of linkage intervals in 125 unrelated MRX
families, Ropers and others previously showed that 30% of all
mutations cluster on proximal Xp.11 We report here the
identification of a new gene, PHF8 (PHD finger protein 8),
located in Xp11 and mutated in families with XLMR
associated with cleft lip/cleft palate.
METHODS
Patients and families
The family pedigrees are shown in figs 2 and 3. DNA and
RNA were extracted from blood samples and immortalised
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lymphoblastoid cell lines (family N42) that were established
from peripheral lymphocytes using standard protocols.
Fluorescence in situ hybridisation (FISH)
BACs on chromosome Xp11.21 were selected from Ensembl
database (http://www.ensembl.org) and the UCSC genome
browser (http://genome.ucsc.edu) and obtained from the
CHORI Institute (http://bacpac.chori.org). Hybridisation
experiments were carried out as previously described.12
Mutation analysis of PHF8
Polymerase chain reaction (PCR) was carried out in 50 ml
reaction volumes containing 100 ng of genomic DNA from
the patients, 10 pM of each primer, 1.25 mM of dNTPs, 0.5 U
Taq DNA polymerase (Promega, Madison, Wisconsin, USA),
and 1.5 mM MgCl2. An initial denaturation of five minutes at
94˚C was followed by 30 cycles of one minute at 94˚C, one
minute of annealing, a one minute extension at 72˚C, and a
final extension step of seven minutes at 72˚C. The products
were then checked on a 1.5% agarose gel to verify
amplification before analysis by denaturing high performance liquid chromatography (DHPLC) using the WAVE
3500 HT system (Transgenomic, Santa Clara, California,
USA). For each amplified exon, melting profiles and
temperatures were predicted by the Transgenomic
Navigator software version 1.5.1 (DHPLC conditions available
upon request). Pairs of amplified fragments from patient and
control PCR products were pooled, denatured at 95˚C for
three minutes, and cooled to 40˚C in decreasing increments of
0.05˚C per second. The products were then injected and
eluted with an acetonitrile gradient at a flow rate of 1.5 ml/
min, with a mobile phase composed of two buffers (buffer A,
0.1 M triethylammonium acetate or TEAA; buffer B, 0.1 M
TEAA with 25% acetonitrile). For each sample pair that
showed an abnormal elution profile, the PCR products were
purified and sequenced on an ABI377 DNA sequencer (Perkin
Elmer, Norwalk, Connecticut, USA).
RT-PCR and expression studies
For reverse transcriptase polymerase chain reaction (RT-PCR)
experiments on mouse material, total RNA samples were
prepared from embryonic, newborn, and postnatal (P60)
mouse brains. Cells were derived from brains of randomly
bred Swiss mice. Glial cells were from newborn murine
cerebral hemispheres, and 95% of the cells were identified as
type 1 astrocytes. Cultures of neuronal cells were set up from
single cell suspension of fetal brains at 15 days of gestation.
Cultures consisted predominantly of neurones (.95%).
Abbreviations: DHPLC, denaturing high performance liquid
chromatography; FISH, fluorescence in situ hybridisation; MRX, nonsyndromic forms of X linked mental retardation; MRXS, syndromic forms
of X linked mental retardation; XLMR, X linked mental retardation
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Letter to JMG
781
Figure 1 Characterisation of the PHF8 gene. Transcriptional map of the Xp11 area including the X chromosomal breakpoint of the t(X;14)
translocation. The minimum critical region is estimated at 220 kb and includes the PHF8 gene that is transcribed from centromere to telomere.
Amplification by RT-PCR was carried out according to
standard procedures.
Non-radioactive in situ hybridisation was undertaken as
described elsewhere.19 Mouse embryonic (16 days postconception) and adult brain sections were hybridised with the
sense and the antisense RNA generated from the 39
untranslated part of Phf8.
RESULTS
Characterisation of the PHF8 gene and identification
of mutations in families with XLMR and cleft lip/cleft
palate
We previously investigated a balanced translocation
(X;14)(p11.2;p10) found in two half sisters and their mother
who all had non-syndromic mental retardation and epilepsy.
To establish the physical location of the chromosomal
aberration, we carried out FISH experiments with BAC
clones obtained from the CHORI institute. The DNA clones
were prepared by standard techniques, were labelled by nick
translation, and were used as probes in FISH, as previously
described.12 The breakpoint of the chromosome 14 was
located on the short arm. As rearrangements of the short
arms of acrocentric chromosomes, particularly robertsonian
translocations, do not lead to any abnormal phenotypes, we
suggested that the Xp chromosomal breakpoint would
probably be involved in the phenotype of the patients. We
localised the Xp breakpoint within the BAC clone RP13444K19 (GenBank Accession number AL732374) (fig 1).
BLAST analysis of the genomic region revealed the presence
of only one cDNA called KIAA1111 (GenBank accession
number AB029034). It is expressed in human adult brain and
represents a novel gene named PHF8 (PHD finger protein 8)
(GenBank accession number NM_015107) (fig 1).
Based on these findings, the PHF8 gene appeared to be a
strong candidate for XLMR. We screened the PHF8 gene for
mutations in 40 families with XLMR and with a linkage
interval covering the candidate region in Xp11. The families
were collected by the EuroMRX consortium (24 families) and
the Greenwood Genetic Center/University of Miami XLMR
study (16 families).13 We analysed the coding sequence of
PHF8 by PCR experiments using genomic DNA and primers
that amplified both the exonic sequences and the exon-intron
junctions (table 1).
Initially, we identified a mutation in PHF8 in family N42,
previously described by Siderius et al.14 Affected males of this
family have a syndromic form of XLMR associated with cleft
Table 1 Primers for mutation detection and polymerase chain reaction amplification
conditions
Exon
Forward primer (59R39)
Reverse primer (59R39)
Annealing temperature
( ˚C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
tcaagtcacttggcttctcga
actgagggttggtgcaagg
acagcactgttctagacctca
gctcaggcctttgttcttggt
gtggcagcctccaataag
ggactgatgaggggacaagaga
gctgtggggtattttattcaggc
gttttggagcatgggagaaa
ttgagatgagtaggtagtggaga
catccagaacaaaacctgattc
gttgtcttaacaaaagtccca
tctccattgaattgccttgg
aggaacagacctctgctgtta
ccagtgaaaccagagggaact
cttgctagcgactaacaatac
Gtatttggctgaaatgctaatc
tcatcgcccctgtactggg
gatgaccgatttactctgacag
tcattctatcttcaccctttg
agagcttggaggtagggaat
gtctagttagttcctttcctgg
ttggtgccagatttgatgttg
atgagaggaggtgaactcggt
gagagcaagtgaacacacctg
cctttcctttgtctctcctct
gggaaagctgggaagaggt
aaacagattggaggggaagg
agagaaacacgaatatacactag
gattcaaaatgtttctgtgctgc
ttaatatgctgtggggccaa
ccttctacattatactcctcact
tatcatgtcttgactgcgttac
ctctccaaaacatctaccca
atgctaactgcagaggcctaa
ggatagcctgctttttgaaac
ctgtctcagtggcatattacc
tccgtctcaaaacaaacaaaca
ccaactagaatgacaatctgtc
ctgattggctgacctggcac
gatggagactgggactgagg
catccttgtctatttcctcct
tctaagtcaaactgctattagt
taagatccttcggttctacaacc
gaaggcaggcaggatgctcta
62
63
56
63
59
59
59
60
58
59
60
58
59
59
62
59
64
64
59
59
59
63
Note: the coding sequence of PHF8 begins at exon 2 and ends at exon 22.
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782
Letter to JMG
Figure 2 Mutation of PHF8 in family N42 associated with X linked mental retardation and cleft lip/palate. (A) Pedigree of family N42 showing the
affected male patients (black squares) who carry the 12 bp deletion (del), the unaffected male and female patients (white squares, N), and the
heterozygous female carriers (N/del). The sequencing electrophoregrams show that the deletion causes the elimination of the splice donor site of intron
8. (B) Reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing results of both PHF8 transcripts expressed in lymphoblastoid cell lines
of individual IV-3. One microgram of RNA from affected individual IV-3 and control was reverse transcribed followed by polymerase chain reaction
(PCR) with one forward primer (59- TAACCTTGTGGAGACACCGAA-39) located in exon 7, one reverse primer (59-AAGAGCAGATGATCGCAACT39) located in intron 8, and a second reverse primer (59-CTAGTGCTAATGCACATCAG-39). In the same reaction, a RSK2 transcript fragment (486 bp)
was amplified as an internal control,10 using the following primers (forward 59-GGACAGCAAATTATGGATGA-39 and reverse 59CTAGTGCTAATGCACATCAG-39). The PCR products were migrated in a 1.2% agarose gel and showed two PHF8 transcripts in the affected individual,
one weakly expressed transcript (transcript 1 fragment, 822 bp) with the 8 bp deletion compared to the control, and a higher expressed transcript
(transcript 2 fragment, 1068 bp) composed of coding sequence of exon 7 extended into intron 8, and absent in the control lane.
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Letter to JMG
783
Figure 3 631CRT (R211X) mutation in family 2. Representation of the pedigree of the Italian family and facial features of patient III-2 (written consent
from the patient and his legal guardian was obtained for publication of the images in print and online). The chromatogram of the mutant sequence is
shown, along with a control sequence. A CRT substitution located in exon 7 was identified in blood DNA from patient III-2. The carrier females (I-2 and
II-2) are heterozygous for this mutation. (Photograph reproduced with patient’s consent.)
lip/cleft palate. The family consists of three affected males in
two generations (III-9, IV-3, and IV-8; fig 2A), who showed,
at the time of clinical examination, mild to borderline mental
retardation, minor facial anomalies such as a long face and
broad nasal tip, cleft lip/cleft palate in two (bilateral for
individual III-9 and unilateral for IV-3), and large hands
(75th to 97th centile for IV-3; .97th centile for IV-8 and III9). Previous linkage analysis assigned the putative XLMR
gene to Xp11.3–q21.3, between the markers DXS337 and
DXS990, defining a linkage interval of 25 cM.14 The mutation
analysis for PHF8 in the three affected males of N42 family
revealed a 12 base pair (bp) deletion at the exon 8/intron 8
junction (fig 2A), that was predicted to suppress the splice
donor site of intron 8. To test the presence of an abnormal
splicing event, RT-PCR was carried out on RNA extracted
from lymphoblasts of both the affected individuals and
controls. The RT-PCR analysis showed the presence of two
transcripts in the affected individuals. One was a very weakly
expressed transcript composed of a portion of exon 8, joined
to the normal exon 9. A higher expressed second band was a
transcript in which the coding sequence extended into intron
8 up to a stop codon (fig 2B).
Based on this finding, additional screening of cases with
mental retardation plus cleft lip/cleft palate was undertaken.
As a result, another mutation was found in a second family
with males who had mental retardation and clinical features
similar to the N42 family (fig 3). The propositus (III-2) was
the second child of two unrelated parents. Two maternal
uncles died in the neonatal period and the mother stated
they had bilateral cleft lip and palate. A third maternal uncle,
who died in a car accident, suffered from mild mental
retardation without clefting. The propositus was born by
spontaneous delivery after an uneventful pregnancy. At
birth, his weight was 2550 g (5th to 10th centile), length
47 cm (10th to 25th centile), and head circumference 33 cm
(5th to 10th centile). At 25 years old, his weight was 60.5 kg
(25th to 50th centile), and his height was 178 cm (75th
centile). He had mental retardation and minor facial
dysmorphia with a scar from an operated cleft lip (fig 3).
He also had long hands (20 cm, .97th centile) with long
and thin fingers, and flat feet with long and thin toes.
Computed tomography and magnetic resonance imaging
were normal. Cytogenetic analysis revealed a normal 46, XY
karyotype, and molecular analysis of the FMR1 CCG expansion, subtelomeric rearrangements and 22q11 deletion by
FISH were negative.
The analysis of the coding sequence of PHF8 revealed the
presence of a nonsense mutation, p.R211X (c.631CRT), in
exon 7 (fig 3), leading to a predicted truncated protein of 211
amino acids compared with the normal protein of 1024
amino acids. We could not test the expression of the altered
transcript as only genomic DNA from the propositus III-2, his
mother, and grandmother were available.
The two mutations described above were present in all
tested affected family members. All female carriers in the
respective families were heterozygous. The sequence changes
were not found in 100 healthy unrelated male and 100
unrelated healthy females (300 X chromosomes), making it
unlikely they were rare polymorphisms.
We also analysed the PHF8 gene in a male patient of a
family affected by the Pallister W syndrome (OMIM
311450)15—which is characterised by median cleft upper lip,
central nervous system involvement with strabismus and
spasticity, and moderate to severe mental retardation—and
in four sporadic male individuals having a similar phenotype
to the two mutated families (that is, mental retardation and
cleft lip/cleft palate). However, no mutations in the coding
sequence of the PHF8 gene were found.
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Letter to JMG
A
Fetal brain
embryonic stage
10.5 12.5 14.5
Neuronal
Cereb
Glial cell line
Hippoc cell line
8d
16.5 18.5 20.5
Control
14d
Phf8
Ophn1
Adult brain
B
MB
NC
MO
OE
OE
T
SG
P IT
L
P IT
PFV
Mouse total embryo 16.5 days pc
OB
Mouse adult brain
St
Co
H
WM
Ce
ML
GL
Figure 4 Expression studies of the mouse orthologue Phf8. (A) Reverse transcriptase polymerase chain reaction analyses carried out on mouse RNA
samples extracted from brains at different embryonic stages, adult brain structures (cerebellum and hippocampus), and neuronal and glial cell lines.
Phf8 was expressed in all tested tissues. (B) In situ hybridisation on mouse embryo (16.5 days postconception (pc) and adult brain section. Nonradioactive in situ hybridisation was carried out as described elsewhere.19 Mouse embryonic and adult brain sections were hybridised with the sense
and the antisense RNA probes generated from the 39 region of the Phf8 gene (cDNA sequence AK122447; primers forward [59AAGGAATGAGGAGGAGCAACA-39] and reverse [59-TCACCACACCCTCTTCAGAG-39]; amplicon of 620 bp). Mouse total embryo: L, lung; MB,
midbrain; MO, medulla oblongata; NC, neopallial cortex; OE, olfactory epithelium; PFV, primordium of follicles of vibrissae; PIT, primordium of incisor
tooth; SG, submandibular gland; T, thymus gland. Mouse adult brain: Ce, cerebellum; Co, cortex; GL, granular layer; H, hippocampus; ML, molecular
layer; OB, olfactory bulb; St, striatum; WM, white matter.
RT-PCR and expression studies
PHF8 is a novel human zinc finger gene of unknown
function. The gene is composed of 22 exons. The transcript
has a length of 5776 bp and an open reading frame of 3075
bp. The PHF8 transcript shows a ubiquitous expression
pattern as tested by expressed sequence tag analyses and
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northern blot hybridisation (results not shown). PHF8
domains are also highly conserved among orthologues in
other species, including mouse and X laevis.
To further investigate PHF8 expression in adult brain and
in primary cultures of mouse neuronal and astroglial cells
during development, we derived appropriate primers from
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Letter to JMG
785
Figure 5 Annotated sequence of the human PHF8 protein. PHF8 protein sequence showing mutations and regions of functional importance. The
positions of the mutations are marked by arrows. PHD fingers (amino acid position 7–53) and JmjC (amino acid position 195–294) domains are
represented by shaded regions. Putative NLS sequences are underlined and italicised.
the mouse homologous gene and studied its expression by
RT-PCR. Figure 4A shows RT-PCR amplification of the mouse
Phf8 mRNA and Ophn1 mRNA used here as a control.16 These
results showed a relatively high level of expression in the
embryonic and early postnatal stages of brain development.
The expression spectrum of Phf8 in sections of mouse
embryos is rather ubiquitous, especially in brain structures,
with a higher expression in neopallial cortex, midbrain, and
the dorsal part of the medulla (fig 4B). The gene is also
expressed in the olfactory epithelium, the submandibular
gland, and the primordium of follicles of the vibrissae. In
addition to the expected expression of Phf8 in fetal brain at
different embryonic stages, a higher expression is observed in
cerebellum (granular layer) and hippocampus in adult brain
(fig 4B), which are structures potentially involved in the
physiological processes underlying memory and learning
abilities.
DISCUSSION
We report here the identification of the human PHF8 gene
located in Xp11.21 and encoding a new member of the PHD
finger protein family. We showed that truncating mutations
of PHF8 led to XLMR with or without cleft lip/cleft palate in
two unrelated families, with a large intrafamilial phenotypic
heterogeneity, ranging from non-specific mental retardation
(N42 family: individual IV-8; Italian family: individual II-5)
to mental retardation and cleft lip/cleft palate (other affected
males of both families).
The PHF8 protein is composed of 1024 amino acids and
contains a PHD zinc finger domain (amino acid positions 7–
53) and a Jumonji C (JmjC) domain (positions 195–294,
fig 5), which are highly conserved among orthologues in
other species, including mouse and X laevis. The murine Phf8
encodes a putative 1005 amino acid protein (Genbank
accession number BAC65729) and shares 94% of identity at
the amino acid level with human PHF8. Furthermore, BLAST
analysis identified an orthologue in yeast (Genbank accession
number NP_010971), suggesting that the PHF8 protein has
been conserved during evolution.
As the large majority of PHD finger-containing proteins are
localized in the nucleus, we looked for protein sorting signals
using the PSORTII prediction program. We found four
putative nuclear localization signals (NLS) with a 4/7
residues pattern, and two bipartite NLS (fig. 5), suggesting
that PHF8 is very likely a nuclear protein. Furthermore,
the predicted truncated proteins in the two affected families
lack five NLS, which probably results in a cytoplasmic
localisation of these truncated proteins thereby altering their
function.
PHD finger genes are thought to belong to a diverse group
of transcriptional regulators affecting eukaryotic gene
expression by influencing chromatin structure. This family
is composed of more than 15 members and one of them,
PHF6, has already been implicated in a syndromic form of
XLMR known as the Börjeson-Forssmann-Lehman syndrome
(MIM 301900).17
More than 250 proteins share the jmjC domain (Interpro
accession number IPR003347). JmjC-domain containing
proteins have been implicated in apoptosis and in chromatin
remodelling.18 The secondary structure of the JmjC domain
predicts an enzyme activity. Its frequent association with
DNA binding motifs, such as PHD finger domains, and its
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786
putative chromatin modification activities suggest a role in
regulating the integrity of the chromatin structure.19
However, the precise enzymatic or biological activity of this
domain remains enigmatic.
The two truncating mutations occur nearby or in the JmjC
domain of PHF8 and are associated with a specific form of
XLMR. Interestingly, mutations in families with XLMR have
been found in the JARID1C gene (MIM 314690), which also
harbours JmjC and PHD finger domains.20 In the JARID1C
gene, several disease causing mutations in XLMR families
have been described that strengthen the importance of this
gene family in the aetiology of mental retardation.
In summary, we have shown that truncating mutations in
the PHF8 gene cause either mild to borderline mental
retardation associated with cleft lip/palate (XLMR–cleft lip/
cleft palate) or non-specific XLMR. PHD finger proteins are
suspected of modifying and regulating the structure of the
DNA, and therefore play a critical role in the regulation of
transcription. The association of PHF8 with mental retardation and midline defects highlights the importance of this
process, specifically during brain development and midline
formation. In further studies we will aim to characterise the
specific function of PHF8 and to understand the consequences of alterations in its function.
GENBANK ACCESSION NUMBERS
Human PHF8 mRNA accession number NM_015107
Human KIAA1111 mRNA accession number AB029034
Human PHF8 protein accession number NP_055922
Mouse Phf8 mRNA accession number AK122447
Mouse Phf8 protein accession number BAC65729
BAC clone RP13-444K19 accession number AL732374
ACKNOWLEDGEMENTS
We thank the patients and their families for their efficient
cooperation in this study. We also thank B Jauffrion for the
establishment of lymphoblastoid cell lines and Dr Doria Lamba for
referring family 2 and the Galliera Genetic Bank for storing patient’s
samples. This work was supported by grants from INSERM,
Fondation France Telecom, Fondation pour la Recherche Médicale
(FL fellowship), GIS Maladies Rares No A02107GS, the 5th European
Union Framework (RTD project QLRT-2001-01810), Telethon Italia
(Grant C51), NICHD (HD26202 to CES), and in part by the South
Carolina Department of Disabilities and Special Needs (SCDDSN).
.....................
Authors’ affiliations
F Laumonnier*, S Holbert*, N Ronce, C Moraine, S Briault, INSERM
U619 ‘‘Génétique de l’autisme et des déficiences mentales’’, Faculté de
Médecine, Université François Rabelais, Tours, France
F Faravelli, Genetica Umana, Ospedale Galliera, Genova, Italy
S Lenzner, H-H Ropers, Max-Planck-Institute for Molecular Genetics,
Berlin, Germany
C E Schwartz, Greenwood Genetic Center, Gregor Mendel Circle,
Greenwood, South Carolina, USA
J Lespinasse, Laboratoire de Génétique Chromosomique, CH
Chambéry, France
H Van Esch, J-P Fryns, Centre for Human Genetics, University of Leuven,
Belgium
D Lacombe, C Goizet, Department of Medical Genetics, CHU Pellegrin,
Bordeaux, France
F P-D Tuy, J Chelly, Institut Cochin, CHU Cochin, Paris, France
H van Bokhoven, B C J Hamel, Department of Human Genetics,
University Medical Centre, Nijmegen, Netherlands
Competing interests: none declared
*These authors contributed equally to the work
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Letter to JMG
Correspondence to: Dr Sylvain Briault, INSERM U619, Génétique de
l’autisme et des déficiences mentales, Faculté de Médecine 10, Bd
Tonnellé BP 3223, 37032 Tours cedex 1, France;
[email protected]
Received 19 November 2004
Revised version received 19 January 2005
Accepted for publication 20 January 2005
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Downloaded from http://jmg.bmj.com/ on June 15, 2017 - Published by group.bmj.com
Mutations in PHF8 are associated with X linked
mental retardation and cleft lip/cleft palate
F Laumonnier, S Holbert, N Ronce, F Faravelli, S Lenzner, C E Schwartz, J
Lespinasse, H Van Esch, D Lacombe, C Goizet, F Phan-Dinh Tuy, H van
Bokhoven, J-P Fryns, J Chelly, H-H Ropers, C Moraine, B C J Hamel and S
Briault
J Med Genet 2005 42: 780-786
doi: 10.1136/jmg.2004.029439
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