2008 Barcelona - European Society of Human Genetics

Clinical genetics
mana, CUCS, Universidad de Guadalajara, Guadalajara, Mexico, 4Doctorado de Genética Humana, CUCS, Universidad de Guadalajara, Jalisco, México.,
Guadalajara, Mexico, 5Hospital México Americano, Guadalajara, Jalisco.
México., Guadalajara, Mexico, 6Hospital Valentin Gomez Farias, Servicio de
Neuropediatría, ISSSTE. Guadalajara, Jalisco, México., Guadalajara, Mexico,
7Instituto Dermatológico de Jalisco Dr. José Barba Rubio, Zapopan, Jalisco,
México., Guadalajara, Mexico.
Neurocutaneous melanosis (NCM) is a rare congenital syndrome
characterized by the presence of Giant Congenital Melanocytic Nevi
(GCMN), either multiple Smaller Congenital Melanocytic Nevi (SCMN),
or both . NCM has characteristically been reported to manifest early in
life, usually by age 2 to 2 .3 years of age and the incidence for asymptomatic
NCM with abnormal MRI is 4 .8% . The Proposita is a 2
years-old, Hispanic female, was the product of the 5th, full-term and
uncomplicated pregnancy; from non-consanguineous parents . She
has a history of Giant Congenital Nevi and several episodes of hydrocephaly
. Clinically, she has Psychomotor delayed; macrocephaly,
hydrocephalus; hemangiomas, multiple congenital pigmented nevi
and a nevus approximately 38 x 30 cm . that covers the lumbosacral
area, lower abdomen and both thighs . This nevus is dark brown and
black colored, with irregular borders; and is covered by thin hair in
some areas . Face, neck, arms, chest, upper back and abdomen are
covered with multiple satellite melancoytic nevi, which measure 1 to 5
cm . in their largest diameter . Palms and soles are not affected . The CT
scan showed dilatation of all ventricles; MRI with gadolinium reported
severe hydrocephalus and there were non-hyperintensity regions . We
concluded that the patient has NCM associated to GCMN and numerous
congenital melanocytic nevi .
P01.245
A deficit of ATP-ase subunit 8 : with contribution for two new
cases
M. Stancheva1 , B. Radeva1 , E. Naumova2 ;
1 2 University Children Hospital, Sofia, Bulgaria, Central laboratory of Clinical
Immunology, UMBAL”Alexandrovska”’, Sofia, Bulgaria.
In two consanguinous children ,brother and sister, was reported a
rare mitochondrial disorder, still not described in literature, caused by
mutation of the gene MT-ATP8: base change T8412C with aminoacid
change : methionin-threonin which lead to dolichocephaly, protruding
metopic sutura, muscle hypotonia , ataxia and mental retardation .The
EEG showed diffuse changes of teta type .The CAT showed atrophy
of the brain of the first child.The investigation of the mother showed
the same mutation which will help the prenatal diagnosis .A treatment
was started with high doses of vit .B1, B6, B12, L-carnitine, coenzyme
Q10 with the aim to stimulate the enzyme processes and compensatory
to increase the ATP by alternative metabolic pathways .The clinical
investigation continues .
P01.246
X-linked α thalassaemia/mental retardation syndrome - a case
with gonadal dysgenesis, caused by a novel mutation in AtRX
gene
A. Jezela-Stanek 1 , C. Fisher 2 , M. Szarras-Czpnik 3 , R. J. Gibbons 2 , M. Krajewska-Walasek
1 ;
1 Department of Medical Genetics, The Children’s Memorial Health Institute,
Warsaw, Poland, 2 MRC Molecular Haematology Unit, Weatherall Institute of
Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom, 3 Department
of Endocrinology, The Children’s Memorial Health Institute, Warsaw,
Poland.
X-linked α thalassaemia/mental retardation (ATR-X) syndrome is one
of the genetic conditions that results in X-linked mental retardation . Its
principal features are: learning difficulties, microcephaly with characteristic
facial features (hypertelorism, nose with flat bridge and triangular,
upturned tip, full, everted lower lip) and α thalassaemia. Other
known traits of ATR-X are genital abnormalities, the severity of which
varies from cryptorchidism to ambiguous genitalia . We present a family
referred to the genetic service with suspicion of Smith-Lemli-Opitz
(SLO) syndrome after the birth of a child with facial dysmorphism, atrioventricular
defect and ambiguous genitalia . Unfortunately, he died before
diagnostics . In a subsequent pregnancy, chromosomal analysis
showed the foetus had a normal male karyotype (46, XY) and SLO
syndrome was also excluded . However, at birth the baby exhibited the
same spectrum of clinical features as in the previous child . Amongst
other abnormalities, external female genitalia and dysgenetic testes
were detected . He was screened for subtelomeric aberrations but no
rearrangements were identified. Observed genital anomalies, together
with the distinct facial appearance and the presence of Haemoglobin H
inclusions in the red blood cells, led to a diagnosis of ATR-X syndrome .
Further molecular study revealed a novel mutation in ATRX (c .G590>T,
p .Cys197Phe), coding for a change from a highly conserved cysteine
to a phenylalanine residue. The same mutation was identified in the
mother, so we can speculate that her elder child was also affected with
ATR-X syndrome .
Work was supported by KBN 2P05A 161 28 and PBZ- KBN-122/
P05/01-10 .
P01.247
cADHERiN-11 as a possible candidate gene for autism
A. Crepel 1 , H. Peeters 1 , J. R. Vermeesch 1 , J. Steyaert 2 , D. Walleghem 3 , K.
Devriendt 1 ;
1 Center for Human Genetics, Leuven, Belgium, 2 Dept. Child Psychiatry, Leuven,
Belgium, 3 University Center for Child and Youth Psychiatry, Antwerp, Belgium.
Background:
Positional cloning of chromosomal translocation breakpoints in autism
patients is a valuable strategy towards the identification of candidate
genes, especially in isolated autism, and when the aberration is de
novo and family history is negative for autism . (1)
Objectives:
We describe a nondysmorphic patient with autism and full scale IQ
of 76, who carries a complex translocation involving chromosomes
3,5,16 and a pericentromeric inversion on chromosome 4 .
Methods:
1Mb BAC array-CHG was performed to uncover possible submicroscopic
imbalances. The breakpoints were finemapped with FISH.
Results:
On array-CGH, a ~1Mb microdeletion encompassing the clone NON-
SC8G10 was detected . Only 1 gene, cadherin-11 (CDH11) was located
in this region . Of the remaining 6 breakpoints, one disrupted the
AK13094 gene, another was near GFOD and RANBP10 .
Conclusions:
In this patient with a complex chromosomal aberration, the CDH11
gene was found to be heterozygously deleted . Cdh11 is expressed in
the lymbic system and hippocampus in mice and may play a role in the
organisation of central synapses . (2) Interestingly, there is evidence that
altered synaptogenesis is implicated in the pathogenesis of autism .
For instance, the cell adhesion molecules NLGN-3 and -4 are implicated
in autism through their role in the establishment of functional
presynaptic terminals in contacting axons . (3) Thus, CHD11 represents
both a positional and functional candidate gene for autism . Mutation
screening in a larger cohort of autism patients is ongoing .
(1) Castermans (2003) J Med Genet 40(5) 352-6
(2) Manabe (2000) J Mol Neurosci 15(6) 534-46
(3) Persico (2006) Trends Neurosci 29(7) 349-58
P01.248
FMR1 gene: prevalence of premutation and intermediate/grey
zone alleles in an autistic Basque sample
I. Arrieta Saez 1 , O. Peñagarikano 2 , M. Télez 1 , M. Barasoain 1 , I. Huerta 1 , J.
Ramírez 1 , B. Criado 3 , P. Flores 4 , A. González 5 ;
1 Dpto Genetica, Antropología Fisica y Fisiologia animal Facultad de Ciencia y
Tecnología, Bilbao, Spain, 2 Emory University School of Medicine, Atlanta, GA,
United States, 3 High School Da Maia, CESPU, Porto, Portugal, 4 Dpto de enfermería,
Escuela de Enfermería, Bilbao, Spain, 5 Dpto Medicina Interna, Facultad
de Medicina, Bilbao, Spain.
Fragile X Syndrome (FXS) is associated with an unstable CGG repeat
sequence in the 5’ untranslated region of the first exon of the
FMR1 gene . The location of this gene coincides with a Fragile Site
(FS) FRAXA . The CGG sequence is polymorphic with respect to size
and purity of the repeat . Although only the full mutation (>200 CGG) is
associated with clinical expression of FXS, premutation (55-200 CGG)
and intermediate/grey zone allele carriers (35-54 CGG) have been
also associated to distinctive phenotypes, one of these are mental retardation
and/or autism . Autism is a behavioral disorder of early onset
marked by social and cognitive deficiencies. Our Previous studies of
chromosomal fragility in autistic and normal individuals show higher
frequency of FS and FRAXA full mutation in autistic individuals . The