2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.099
Deletion of MAOA and MAOB only in a male patient causes
severe developmental delay, intermittent hypotonia and
stereotyped hand movements.
A. Whibley 1 , L. Willatt 1 , J. Dore 2 , L. Gaunt 2 , P. Tarpey 3 , M. Stratton 3 , D. Donnai
2 , F. Raymond 1 , I. GOLD 1 ;
1 Cambridge Institute for Medical Research, Cambridge, United Kingdom, 2 Regional
Genetics Service, St. Mary’s Hospital, Manchester, United Kingdom,
3 Sanger Institute, Hinxton, Cambridge, United Kingdom.
The monoamine oxidases MAOA and MAOB are isoenzymes which
catalyse the oxidative deamination of biogenic amines, with substrates
including the neurotransmitters norepinephrine, serotonin and dopamine
. A number of behavioural traits, such as aggressive and antisocial
behaviour, and psychiatric conditions, such as schizophrenia and
bipolar disorder, have been associated with MAOA/B dysfunction and
genetic variation at these loci .
The MAOA and MAOB genes occur in tandem but in opposite orientations
on Xp11 .23 . The two genes share 70% identity at the amino
acid level and exhibit identical organisation of their 15 exons . Previous
reports of MAOA and MAOB deletions have encompassed the
adjacent NDP gene . Mutations in NDP cause Norrie disease, a disorder
characterised by blindness, progressive sensorineural deafness
and, frequently, mental retardation . Genotype-phenotype correlations
in Norrie disease suggest that deletions of NDP which also extend
to the MAOA/B genes result in a more severe neurological phenotype
. However, the phenotypic contribution of MAOA/B gene disruption
is difficult to dissect in this context. Here we report an individual
with a submicroscopic deletion which encompasses only the MAOA
and MAOB genes . The 246kb deletion, which includes exons 2-15 of
MAOA and the entire coding region of MAOB, was detected by highresolution
long oligonucleotide X chromosome array comparative genomic
hybridisation, and confirmed by fluorescence in situ hybridisation
. The phenotype of the affected boy was severe mental retardation
with unusual hand posturing . The obligate mother of the affected boy
was clinically normal .
P01.100
Raised t3 levels and mutations in MCT (SLC A ) cause Xlinked
cerebral palsy and mental retardation
L. Raymond 1 , A. Whibley 1 , S. Price 2 , E. Rosser 3 , N. Rahman 4 , S. Holder 5 , F.
Stewart 6 , P. Tarpey 7 , A. Futreal 7 , M. Stratton 7 , I. GOLD 1 ;
1 Cambridge Institute for Medical Research, Cambridge, United Kingdom, 2 Oxford
Regional Genetics Service,, Oxford, United Kingdom, 3 Institute of Child
Health, University of London, London, United Kingdom, 4 Institute for Cancer
Research, London, United Kingdom, 5 Northwick Park Hospital, London, United
Kingdom, 6 Northern Ireland Regional Genetics Centre, Belfast, United Kingdom,
7 Sanger Institute, Hinxton, Cambridge, United Kingdom.
Mutations or whole gene deletions of MCT8 (SLC16A2) were identified
in males with raised serum T3 concentrations and severe psychomotor
retardation . The associated phenotype prompted us to screen
MCT8(SLC16A2) in males with X-linked mental retardation with spastic
quadriplegia and those with XLMR alone. We have identified 3 mutations
( 1018delC, A224T,R271H) and 2 single exon deletions (exon
1 and exon 6) in families with X-linked spastic quadriplegia and severe
mental retardation but did not find any mutations in >300 families
where mental retardation alone was the presenting feature .
Prior to identification of the mutation all cases were all described as
severe cerebral palsy . Males present with severe hypotonia at birth
and develop a severe spastic quadraplegia in all cases within the first
year of life that remained static once it had evolved . Brain MRI in one
affected individual was normal . None of the affected individuals were
able to walk independently or had intelligible speech and all needed
full-time care either in institutions or at home. Difficulties with weight
gain and difficulty feeding are consistent features. Thyroid hormone
profiles were performed in all families once sequence variants in the
MCT8(SLC16A2) gene were identified. Carrier females were found to
have free T3 levels at the upper limit of normal between 7 .0 and 7 .5
(3 .0-7 .5) pmol/l whereas the affected males were found to have raised
T3 levels 9 .6 - 13 .7 (3 .0-7 .5) pmol/l . Free T4 and TSH levels were
within the normal range in all affected males and carrier females .
P01.101
Duplications of the mEcP2 gene region and severe mental
retardation in males
R. I. Lewis, L. P. Lazarou, S. Morgan, H. L. Archer, S. J. Davies, A. J. Clarke,
R. Butler;
Institute of Medical Genetics, Cardiff, United Kingdom.
Mutations in the MECP2 gene are associated with Rett syndrome in
females and a spectrum of neurological disorders in males, from mild
mental retardation to severe neonatal encephalopathy . More recently,
duplications of the MECP2 gene have been described in males with
severe mental retardation and a range of other progressive neurological
symptoms. Using the multiplex ligation-dependent probe amplification
(MLPA) assay, we have screened 20 male patients who have
been specifically referred for MECP2 gene duplication analysis, with
symptoms including severe mental retardation, epilepsy and an “Angelman
like” phenotype . Duplications involving the MECP2 gene were
detected in five cases (25%), four of these being in unrelated males
and one in a similarly affected brother . Two of the unrelated cases
show complex rearrangements of the MECP2 gene . These results and
others that have been published recently, show rearrangement of the
MECP2 gene to be a relatively common mutation mechanism in males .
This redefines the testing criteria for referral for MECP2 analysis. We
will attempt to further determine the clinical phenotype for males with
MECP2 gene duplications, to help improve service provision .
P01.102
A study on the most common Genes involvement among iranian
Families Who Have REtt syndrome
M. Dehghan Manshadi, M. Rostami, T. Majidizadeh, M. SeydHasani, M.
Houshmand;
Special Medical Center, Tehran, Islamic Republic of Iran.
MECP2-related disorders include classic Rett syndrome, variant or
atypical Rett syndrome, and mild learning disabilities in females and
neonatal encephalopathy and mental retardation syndromes in males .
Classic Rett syndrome is a progressive neurologic disorder in girls
characterized by normal birth and apparently normal psychomotor development
during the first six to 18 months of life. The girls then enter a
short period of developmental stagnation followed by rapid regression
in language and motor skills . Seizures occur in up to 90% of affected
females; generalized tonic-clonic seizures and partial complex seizures
are the most common . Females with classic Rett syndrome typically
survive into adulthood, but the incidence of sudden, unexplained
death is significantly higher than in controls of similar age. Atypical Rett
syndrome is increasingly observed as MECP2 mutations have been
identified in individuals previously diagnosed with autism, mild learning
disability, clinically suspected but molecularly unconfirmed Angelman
syndrome, or mental retardation with spasticity or tremor .
Rett syndrome is inherited in an X-linked dominant manner . Approximately
99 .5% of cases are single occurences in a family, resulting either
from a de novo mutation in the child with Rett syndrome or from
inheritance of the disease-causing mutation from one parent who has
somatic or germ line mosaicism .
PCR amplification and Sequencing of the three axons of MECP2 gene
coding region showed that R 407 Stop codon, R 224C and A 72 R were
heterozygote mutations in all Iranian female patients .
P01.103
X-linked mental retardation(XLmR) and the MECP gene
R. G. Goliath, L. Adonis, G. Carvill, M. Urban, K. Fieggen;
Division of Human Genetics, Cape Town, South Africa.
MECP2 is an X-linked gene encoding a nuclear protein that binds specifically
to methylated DNA. Until recently the gene was predicted to
function as a general transcriptional repressor . An alternative function
however has been recently reported indicating the primary function of
MeCP2 not being the silencing of methylated promoters .
Mutations in MECP2 have been reported to be the molecular basis of
a broad spectrum of neurological disorders including : Rett syndrome
(RTT), unexplained progressive encephalopathy and an Angelman-like
phenotype . Also, duplications of MECP2 region are associated with
10% of familial X-linked mental retardation (XLMR) . The XLMR phenotypic
spectrum often includes hypotonia, spasticity, absent speech
and recurrent infections .
To date the Division of Human genetics, University of Cape Town has
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