LETTER TO JMG
The original Lujan syndrome family has a novel missense
mutation (p.N1007S) in the MED12 gene
Charles E Schwartz, Patrick S Tarpey, Herbert A Lubs, Alain Verloes, Melanie M May, Hiba Risheg,
Michael J Friez, P Andrew Futreal, Sarah Edkins, Jon Teague, Sylvain Briault, Cindy Skinner, Astrid
Bauer-Carlin, Richard J Simensen, Sumy M Joseph, Julie R Jones, Josef Gecz, Michael R Stratton,
F Lucy Raymond, Roger E Stevenson
............................................................... ............................................................... .....
J Med Genet 2007;44:472–477. doi: 10.1136/jmg.2006.048637
A novel missense mutation in the mediator of RNA polymerase
II transcription subunit 12 (MED12) gene has been found in the
original family with Lujan syndrome and in a second family
(K9359) that was initially considered to have Opitz–Kaveggia
(FG) syndrome. A different missense mutation in the MED12
gene has been reported previously in the original family with
FG syndrome and in five other families with compatible clinical
findings. Neither sequence alteration has been found in over
1400 control X chromosomes. Lujan (Lujan–Fryns) syndrome is
characterised by tall stature with asthenic habitus, macroce-
phaly, a tall narrow face, maxillary hypoplasia, a high narrow
palate with dental crowding, a small or receding chin, long
hands with hyperextensible digits, hypernasal speech, hypoto-
nia, mild-to-moderate mental retardation, behavioural aberra-
tions and dysgenesis of the corpus callosum. Although Lujan
syndrome has not been previously considered to be in the
differential diagnosis of FG syndrome, there are some over-
lapping clinical manifestations. Specifically, these are dysgen-
esis of the corpus callosum, macrocephaly/relative
macrocephaly, a tall forehead, hypotonia, mental retardation
and behavioural disturbances. Thus, it seems that these two X-
linked mental retardation syndromes are allelic, with mutations
in the MED12 gene.
separate entities on clinical criteria alone.1Notable among the
XLMR syndromes so linked are those associated with muta-
tions in L1 cell-adhesion molecule , aristaless-related homoeo-
box, X-linked nuclear protein, filamin A and polyglutamine
tract binding protein 1 genes.1–7In some instances, the linked
syndromes have overlapping clinical manifestations (eg, L1
cell-adhesion molecule gene mutations in MASA (mental
retardation, aphasia, shuffling gait, adducted thumbs) syn-
drome, X-linked hydrocephaly and spastic paraplegia type 1),
and in other instances the linked entities exhibit rather
disparate clinical presentations (eg, filamin A gene mutations
in periventricular nodular heterotopia, Melnick–Needles syn-
drome and otopalatodigital syndrome).1 6 7
A recurrent mutation (c.2881CRT, p.R961W) in exon 21 of
the mediator subunit 12 gene (MED12, also known as HOPA
and TRAP230) has been found in the original family with FG
syndrome and in five other families with compatible clinical
findings.8In this communication, we report that the original
family with Lujan syndrome (also known as Lujan–Fryns
syndrome and XLMR with Marfanoid features) has a separate
sequence alteration (c.3020ARG, p.N1007S) in exon 22 of the
dentification of the gene mutations responsible for X-linked
mental retardation (XLMR) syndromes has been the domi-
nant force in linking syndromes previously considered as
MED12 gene. It seems that these two XLMR syndromes,
previously considered separate and phenotypically distinct,
are allelic, with different mutations in the MED12 gene.
Figure 1 shows an updated partial pedigree of kindred 8295
(K8295), the original family described as having Lujan
syndrome.9An additional affected individual (V-9) has been
born since the initial family report, and one individual (IV-9)
previously considered to be affected is now found to be
phenotypically different from the affected males. Table 1
summarises the measurements, clinical findings and intelli-
gence quotient (IQ; as determined by the Stanford–Binet
Intelligence Scale10) in affected males. The affected males IV-2,
IV-5 and V-9 were >8 cm taller than their fathers, and IV-12 was
as tall as his father. Table 2 gives a comparison of the findings in
Lujan syndrome with those in FG syndrome. Carriers had normal
craniofacies, ranged in height from 160 to 173 cm (35–95th
centile) and had head circumferences from 54.9 to 57.6 cm (60–
97th centile).Their IQ measurements (Kaufman Brief Intelligence
Test)11ranged from 83 to 102. Four affected males and two carrier
females had thyroid function studies (serum thyroid-stimulating
hormone, free and total triiodothyronine, free and total thyrox-
ine), all of which were normal.
IV-2 was aged 17 years when initially reported. He was re-
evaluated at ages 27 and 41 years. He had no malformations,
but did have dysmorphic facies, broad thumbs, hyperextensible
joints, mild pectus excavatum, flexion contractures at the right
elbow and both knees, global developmental delay, seizures,
hypotonia and hypernasal speech (fig 2). In addition, he had
macrocephaly, a keel-shaped forehead, a long narrow face,
minimally downslanted palpebrae, an open mouth, a tall
narrow palate, crowded teeth, a small chin and abnormal ears
(flattened superior helix on the right, deficient folding of lateral
helix on the left, absent lobes). Testes were small (13 ml, 6 ml).
In his youth he was aggressive, but is now more passive. He
lives in a group home. His IQ was 42.
IV-5 was evaluated multiple times between the ages of 4 and
35 years. He had global developmental delay, hypotonia,
hypernasal speech and an easy-going personality. He had a
febrile seizure in infancy. He had macrocephaly and a long
narrow face with high nasal root, ptosis, unfolded left helix,
irregular right lateral helix, a short philtrum with prominent
philtral pillars, an open mouth, a tall narrow palate, crowded
teeth and a small jaw (fig 2). He was tall and asthenic, the
wrists and fingers were mildly hyperextensible, the thumbs
Abbreviations: FG syndrome, Opitz–Kaveggia syndrome; IQ, intelligence
quotient; K8295, kindred 8295; MED12, mediator of RNA polymerase II
transcription subunit 12; XLMR, X-linked mental retardation
were not broad and there was no pectus abnormality. He lives
in a group home. His IQ was 60.
IV-12 was aged 19 years when initially reported and was re-
evaluated at ages 29 and 42 years (fig 2). He had global
developmental delay and behavioural problems. He had
macrocephaly, dolichocephaly, a tall narrow face with promi-
nent forehead, a high nasal root, hypotelorism, a narrow nose, a
flat mid-face, a high narrow palate, crowded teeth and a
swollen lower face (due to dental infection, at least on the
right). The hands and fingers were long, and the thumbs were
broad. The large joints were not hyperextensible, but the fingers
were. Testes measured 26.5 ml bilaterally, and bilateral
varicoceles are present. IV-12 is married to an intellectually
impaired woman and they live alone, but under supervision. He
is quite anxious, obsessive–compulsive, talks constantly and
seeks attention. His IQ was 59.
V-9 was born after the initial report and was evaluated at
ages 10 and 23 years. He has been diagnosed with Asperger
syndrome. He was hyperactive, spoke loudly with a projected
voice, and was attention seeking and aggressive. He was tall
(.97th centile), with a large head (85th centile), and had large
hands and feet. The face was tall and narrow with a normal
nose, short philtrum and tall palate (fig 2). There was no chest
deformity. There was no history of hypotonia; the joints were
not hyperextensible but the feet were flat. The testes were
approximately 25 ml (comparison with Prader beads). His IQ
In the original report, IV-9 was considered to be affected,
although he differed from the other affected males in that he
lacked an asthenic habitus and long hyperextensible digits and
had more severely impaired cognitive function. He was re-
evaluated at 42 years and was found to be quite different from
IV-2, IV-5, IV-12 and V-9. He never developed speech and was
unable to attend school or undergo cognitive testing. He was
not hypotonic nor did he drool. He was considered aloof, had a
fixation on newsprint and shapes, rocked from side to side, had
a high level of anxiety, was constantly moving and was not
aggressive. He had normal height (65th centile) and head size
(55th centile), normal hand length (50th centile) and was said
to have the facial appearance of his father. He had male pattern
balding, downslanting palpebral fissures, a prominent nasal
root, and no facial hypotonia. Musculoskeletal examination
was normal. Vineland Adaptive Behavior Scale assessment gave
a score of ,20.12
The proband was one of six siblings (partial pedigree shown in
fig 1). One sister required special education and two maternal
nephews (III-2 and III-3) had mental retardation.
II-5, the proband, had global developmental delay. Agenesis
of the corpus callosum was found on cranial tomography.
Examination at 19 years of age showed a small head (54 cm,
3rd centile), a long narrow face with high square forehead, a
bulbous nasal tip, flat malar area, a short philtrum, a bowed
upper lip, a prominent lower jaw and a hairy nevus on the right
forearm. The testes appeared large. He was considered to have
moderate to severe cognitive impairment. His speech was
limited and difficult to understand. Behaviour was marked by
temper tantrums and aggressiveness. His findings were initially
considered to be consistent with FG syndrome.
III-2 had a birth weight of 3450 g and a length of 50 cm at
term delivery. He experienced global developmental delay of
moderate severity and had a tendency to opisthotonic posturing
during early childhood. As a teenager he was tall and slender,
with a long face and high forehead, short philtrum, small
mouth and narrow palate, and crowded teeth (table 1 and fig 3).
showing four affected males in two
generations, and K9359 showing three
affected males in two generations. The
numbering in K8295 is the same as in Lujan
et al.9Note that individual IV-9 (hatched
square) has mental retardation, but is
different phenotypically from the affected
males and does not have the p.N1007S
MED12 mutation. The horizontal bar above
a symbol indicates an individual evaluated.
A, wild-type allele at nucleotide 3020; G,
mutant allele at nucleotide 3020; A/G,
carrier female. XI indicates the ratio of active
to inactive allele in female carriers.
Partial pedigrees of kindred 8295
Lujan syndrome and MED12 mutation473
He was moderately mentally retarded and was hyperactive with
outbursts of aggressiveness. Brain CT, EEG and hearing tests
III-3 was born at 34 weeks with a weight of 2450 g and a
length of 48 cm. Development was globally delayed with
walking at 2 years and first words at 4K years. He was tall
and thin, had scaphocephaly with a narrow face, upslanting
palpebral fissures, a short philtrum and micrognathia (table 1
and fig 3). He had moderate mental retardation with limited
verbal abilities and attention deficit hyperactivity disorder.
Cranial MRI was normal.
As part of a systematic sequencing screen of 737 Vega
annotated genes in 250 families with XLMR, a base alteration,
c.3020ARG, was observed in the proband from the original
Lujan syndrome family, K8295.9 13This change was subse-
quently confirmed to segregate with the Lujan phenotype in the
family. Additionally, the alteration was not observed in 734 X
chromosomes from normal males studied at the Greenwood
Genetic Center, Greenwood, South Carolina, USA, nor in 719
control X chromosomes (227 males, 246 females) sequenced
at the WellcomeTrust Sanger Institute,
X-Inactivation studies of carrier mothers did not detect
skewing. The same alteration was found in the three affected
males and the one available carrier female in K9359.
The c.3020ARG change results in the substitution of a serine
residue for an asparagine at position 1007 (p.N1007S) in exon
22. The asparagine residue is contained within a region that is
highly conserved in vertebrates.
Lujan syndrome and FG syndrome are among the XLMR
syndromes that have posed the greatest diagnostic challenges
for clinicians.9 14–18Individuals with Lujan syndrome have tall
stature with asthenic build, macrocephaly, a tall narrow face,
maxillary hypoplasia, a high narrow palate with dental
crowding, a small or receding chin, long hands with hyper-
extensible digits, hypernasal speech, hypotonia, mild-to-mod-
erate mental retardation,
(hyperactivity, emotional lability, shyness, aggressiveness,
autistic mannerisms and/or psychoses) and agenesis/dysgenesis
of the corpus callosum. In FG syndrome, the major findings
are agenesis of the corpus callosum, relative macrocephaly,
facial dysmorphism (frontal hair upsweep, a high prominent
Measurements and clinical manifestations in affected males in kindred 8295
IV-2 IV-5 IV-12V-9 II-5III-2III-3
Height, cm (centile)
Span, cm (centile)
Weight, kg (centile)
Interpupillary, cm (centile)
Hand length, cm (centile)
Ear length, cm (centile)
Agenesis of corpus callosum
Tall narrow face
High full nasal root
High narrow palate
Second toe longer
Testicular volume, ml
IQ (Stanford–Binet IV)
186.7 (95) 181 (80)
190 (.98) 186.7 (95) NA
– 190.5 (85) NA
59 (80)59 (90)
177 (90) 149 (80)
56.5 (75) 53.5 (45)
21.6 (.98) –
– 5.5 (,3)
IQ, intelligence quotient; K8295, kindred 8295; NA, not applicable.
?CT suggestive of agenesis of the corpus callosum.
`Appeared large; not measured.
and Opitz–Kaveggia syndrome
Comparison of clinical findings in Lujan syndrome
Major distinguishing findings
syndrome FG syndrome
High nasal root
Long hyperextensible digits
Frontal hair upsweep
Persistent fetal finger pads
Horizontal palmar creases
Major findings that overlap
Agenesis of corpus callosum
Tall prominent forehead
High narrow palate, dental crowding
FG, Opitz–Kaveggia syndrome.
474Schwartz, Tarpey, Lubs, et al
forehead, hypertelorism, downslanting palpebrae, small cupped
ears, a thin upper lip and a full lower lip), short hands with
broad thumbs, broad big toes, anal anomalies/constipation,
hypotonia, variable mental retardation and behavioural dis-
turbances. Anal anomalies or constipation, which occur
commonly in FG syndrome, have not been reported in Lujan
syndrome. Tall stature, long hands and fingers, and hypernasal
speech are to be expected in Lujan syndrome, but are absent or
less notable in FG syndrome.
Certain findings—macrocephaly/relative macrocephaly, tall
forehead, tall narrow palate with dental crowding, hypotonia,
mental retardation, behavioural disturbances and dysgenesis of
the corpus callosum—are shared by both syndromes (table 2).
Apart from these similarities, neither of the syndromes has
been considered in the differential diagnosis of the other.19 20
None of the somatic findings is obligatory in either syndrome
and some seem to be common among people with mental
Fryns and van den Berghe16have commented that the muscle
hypotrophy, hypotonia, developmental delay and shyness were
more notable in individuals with Lujan syndrome before
puberty, whereas the Marfanoid habitus, more specifically the
excess of span over height, became obvious only after puberty.
Unfortunately, we do not have span measurements at various
ages in the original family (K8295) to support this observation.
Span centiles were less than height centiles in all the three
adult males in whom measurements were available (table 1). In
K9359, measurements during the teenage years showed that
the span exceeded the height by only 1 cm in the two affected
A spectrum of behavioural disturbances, ranging from
shyness to frank psychosis, has been noted among individuals
with Lujan syndrome.15 16 21Some individuals, however, seem to
be friendly, jovial and outgoing, without overt signs of
In K8295, emotional lability,
excessive talkativeness, attention seeking and anxiety were
evident in two individuals (IV-12, V-9), whereas two others
were more passive and cooperative, at least in adult life. In
K9359, the males were hyperactive and prone to outbursts of
aggression and tantrums.
The occurrence of mental retardation of apparently unrelated
cause in the original family with Lujan syndrome reported here
may be unsettling. Yet, the prevalence of mental retardation
among males in the population (,3%) makes it probable that
at least 1 out of 30 kindreds with XLMR will contain a
minimum of one male with mental retardation of a different
cause than other affected males in the kindred. An additional
ascertainment bias may be seen among kindreds with multiple
males with mental retardation.
The highly conserved MED12 protein, also known as HOPA
and TRAP230, is the largest component of the mediator
complex, which has an essential role in regulating RNA
polymerase II activity.23 24The mediator complex contains a
large number of subunits, some core elements and others like
MED12, that serve as transcriptional facilitators for specific
pathways. A number of studies highlight the importance of
MED12 in model organisms where it seems to be essential for
normal development.25–27Other studies have also implicated
MED12 in specific developmental pathways. Boyer and
colleagues have reported two specific findings that link
MED12 to the Wnt/B-catenin pathway and to the sonic
hedgehog pathway through direct interaction with Gli3.28 29
Another report by Lehner et al30has also featured MED12 (dpy-
22 in Caenorhabditis elegans) as a highly connected ‘‘hub’’ gene
with the potential to enhance phenotypic consequences of
many different forms of genetic variation. The current data,
along with other substantial functional studies, suggest that
at age 17 years has a tall thin face, full nasal root, thin nose, short philtrum
and small mouth. III-3 at age 11 years has scaphocephaly, upslanting
palpebral fissures, short philtrum and micrognathia. The patients and their
legal guardians have provided consent for publication of these
K9359. Facial appearance of III-2 (top) and III-3 (bottom). III-2
views of IV-2, IV-5, IV-12, and V-9. Right column, top to bottom: broad
thumb of IV-12, hand of IV-12 showing hyperextensible joints, narrow
alveolar ridge of IV-12, foot of IV-2 showing the second toe slightly longer
than the big toe. The patients and their legal guardians have provided
consent for publication of these photographs.
Left and middle columns from top to bottom: frontal and profile
Lujan syndrome and MED12 mutation475
MED12 and the entire mediator complex are involved in a
broad range of developmental processes.
The p.N1007S alteration found in Lujan syndrome seems to
significantly affect predicted protein folding domains within
the MED12 protein. The presence of a serine at position 1007
removes a coiled region while also reducing the length of a
b-pleated sheet based on Protean analysis (DNA Star package,
Lasergene, Madison, Wisconsin, USA). Additionally, PolyPhen
(http://tux.embl-heidelberg.de/ramensky/) analysis predicts the
p.N1007S substitution to be possibly deleterious.
The evidence that Lujan syndrome is caused by the p.N1007S
alteration in MED12 rests with (1) identification of the
alteration in the original family with Lujan syndrome, (2)
identification of the same alteration in a second family with
compatible clinical findings, (3) an earlier report of another
missense variant in MED12 in FG syndrome, an XLMR
syndrome with clinical findings overlapping those of Lujan
syndrome, (4) absence of the missense variation in over 1400
control X chromosomes, and (5) computer protein modelling,
which indicates that the alteration is probably pathogenic.
A certain deference should be accorded kindred 8295, which
is the prototype for Lujan syndrome.9Only those kindreds/cases
with a compatible clinical phenotype and mutations in the
MED12 gene should retain the diagnosis of Lujan syndrome.
Consideration should be given to reclassification for those
kindreds/cases reported subsequent to K8295 that do not have
mutations in the MED12 gene. With this approach, the
phenotypic boundaries of Lujan syndrome (ie, those cases with
mutations in the MED12 gene) may be determined.
We thank the family K8295 for their cooperation over a period of more
than two decades. This work was supported by grants from the National
Institute of Child Health and Human Development (HD 26202 to CES),
the South Carolina Department of Disabilities and Special Needs, the
Wellcome Trust, and the Australian NH and MRC Programs (400121 to
JG). This paper is dedicated to the memory of Ethan Francis Schwartz,
Charles E Schwartz, Herbert A Lubs, Melanie M May, Hiba Risheg,
Michael J Friez, Cindy Skinner, Astrid Bauer-Carlin, Richard J Simensen,
Sumy M Joseph, Julie R Jones, Roger E Stevenson, JC Self Research
Institute of Human Genetics, Greenwood Genetic Center, Greenwood,
South Carolina, USA
Patrick S Tarpey, P Andrew Futreal, Sarah Edkins, Jon Teague, Michael
R Stratton, Cancer Genome Project, Wellcome Trust Sanger Institute,
Alain Verloes, Department of Genetics, Clinical Genetics Unit, Robert
Debre University Hospital, Serurier, France
Sylvain Briault, Laboratoire de Ge ´ne ´tique Chromosomique, Centre
Hospitalier Re ´gional d’Orle ´ans, Orle ´ans, France
Josef Gecz, Departments of Paediatrics and Molecular Biosciences,
University of Adelaide, Adelaide, Australia
F Lucy Raymond, Cambridge Institute of Medical Research, University of
Cambridge, Addenbrookes Hospital, Cambridge, UK
Competing interests: None.
The patients and their legal guardians have provided consent for
publication of the patient images in figs 2 and 3.
Correspondence to: Dr R E Stevenson, JC Self Research Institute of Human
Genetics, Greenwood Genetic Center, 113 Gregor Mendel Circle,
Greenwood, SC 29646, USA; email@example.com
Received 20 December 2006
Revised 23 February 2007
Accepted 27 February 2007
Published Online First 16 March 2007
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and in a second family with compatible findings.
N Lujan syndrome is thus allelic to Opitz–Kaveggia (FG)
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previously found to have mutations in the MED12 gene.
N Lujan syndrome and FG syndrome share certain clinical
findings (dysgenesis of the corpus callosum, macroce-
phaly, a tall forehead, a high palate, hypotonia, mental
retardation and behavioural disturbances). Anal anoma-
lies/constipation are common in FG syndrome, and tall
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are common in families with Lujan syndrome.
476Schwartz, Tarpey, Lubs, et al
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