2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.320
Gene copy Number analysis using semi-quantitative multiplex
PcR-based assay on capillary electrophoresis systems
S. Jankowski, E. Currie-Fraser, L. Xu;
Applied Biosystems, Foster City, CA, United States.
Deletions and duplications in genomic DNA have been implicated as
pathogenic mutations in many diseases . Traditionally, detection of
these types of mutations is done using southern blot hybridization or
Fluorescence in situ hybridization, techniques which can be laborious,
time-consuming and require high quantities of starting material . In
this study we present analysis of a semi-quantitative multiplex PCRbased
method that uses relative quantitation of fluorescently-labeled
fragments . Fragments from BRCA1, BRCA2, 9p21 and MMR (MSH2)
regions were tested using labeled probes from DNA that had been
isolated from blood. Amplified samples were then run on an Applied
Biosystems capillary electrophoresis platform and the data was analyzed
in GeneMapper® software v4 .0 . After signal normalization, loci
regions that had undergone deletions or duplications were identified
using the GeneMapper® software v4 .0 report manager feature and
verified using the dye scale functionality. Our results will highlight an
easy to use, optimal workflow and analysis that can be used for both
small and large-scale studies .
P01.321
A severe form of the X- linked microphthalmia with linear skin
defects syndrome (mLs) in a female newborn - expansion of the
clinical spectrum
E. Steichen-Gersdorf 1 , F. Pientka 2 , D. Kotzot 3 , I. Wimplinger 2 , E. Griesmaier 1 ,
K. Kutsche 2 ;
1 Medical University of Innsbruck, Innsbruck, Austria, 2 Institute for Humangenetics,
Hamburg, Germany, 3 Department of Medical Genetics, Innsbruck, Austria.
The microphthalmia with linear skin defects syndrome (MLS/MIDAS)
is an X-linked disorder with male lethality, mostly associated with segmental
monosomy of the Xp22 region . MLS is characterized by unilateral
or bilateral microphthalmia and linear skin defects limited to the
face and neck . We report a female newborn with a severe phenotype
of MLS syndrome . She presents with the typical MLS signs, such as
bilateral microphthalmia, primary persistent vitreous and sclerocornea,
and a linear erythematous skin defect on her cheek . Additional features
include agenesis of the corpus callosum, left-sided diaphragmatic
hernia, an ileal duplication cyst, imperforate anus with a rectoperineal
fistula, a hamartoma at the right liver lobe, and partial duplication
of the uterus .
A terminal deletion of the short arm of one of her X chromosomes
was confirmed by fluorescence in situ hybridization using various
BAC clones mapping in Xp22 .3-p22 .2 . The breakpoint was localized
in Xp22 .2 and the size of the deletion was estimated to cover ~11 Mb,
including the HCCS gene . Mutations in HCCS, encoding the mitochondrial
holocytochrome c-type synthase, have recently been identified in
patients with MLS and normal karyotype . Midline defects, as imperforate
anus and duplication of the uterus, have rarely been described in
patients with MLS . However, anal atresia is a frequent feature in male
patients with X-linked Opitz G/BBB syndrome carrying a mutation in
MID1 . We hypothesize that deletion of both MID1 and HCCS as well
as skewed XCI might have contributed to the complex disease phenotype
of our patient .
P01.322
corpus callosum Agenesy in three Patients With moebius
syndrome
S. Basaran Yilmaz, E. Karaca, G. Yesil, A. Yuksel;
Istanbul University,Cerrahpasa Medical Faculty, Department Of Medical Genetics,
Istanbul, Turkey.
Moebius Syndrome is a rare dissease which is defined as congenital
facial palsy with impairment of ocular abduction . The facial nerve(7)
and abducens nerve(6) are most frequently involved, but other cranial
nerves may be involved as well . Other variable features include orofacial
dysmorphism, limb malformations, mental retardation, external ear
defects . The most accepted hypothesis with regard to pathogenesis is
that disruption of the primitive subclavian arteries and their branches
before establishment of a sufficient blood supply to the brain stem
leads to the symptoms of Moebius sequence . Up to date congenital
anomalies of the posterior fossa, including Arnold-Chiari malformation,
pineal cyst, hypoplastic hemicerebellum, asymetric lateral ventricles,
anomalies of cranial nerves nucleii had been described .
We describe here 3 cases with Moebius Syndrome in two of whom
corpus callosum agenesis were detected .
The patients referred to our clinic with fasial asymetry and additional
dysmorphic features . Cranial MRI revealed corpus callosum agenesy
in two of the patients .
To our knowledge, these are the first patients with Moebius Syndrome
who are reported presenting corpus callosum agenesy .
P01.323
MOMO syndrome without macrosomia - alternative definition of
the obesity syndrome
N. Tyshchenko1 , T. Neuhann1 , E. Schrock1 , A. Huebner2 , S. Tinschert1 ;
1 2 Institute of Clinical Genetics, Dresden, Germany, Children’s Hospital, Technical
University, Dresden, Germany.
Two unrelated patients with a combination of macrosomia, macrocephaly,
obesity and ocular abnormalities (retinal coloboma and nystagmus)
were described by Moretti-Ferreira et al . (1993) . Thereafter,
the new syndrome - called MOMO syndrome (Macrosomia, Obesity,
Macrocephaly, and Ocular abnormalities) - was categorized as an
overgrowth syndrome . However, since a third patient, published in
2000, was of short stature, overgrowth was discussed as non-mandatory
for the diagnosis .
We report a further patient with proposed diagnosis MOMO syndrome .
At the age of 5 years and 7 months the girl presented with overweight,
macrocephaly and borderline short stature . She showed a prominent
forehead, deep-set eyes, a flat nasal bridge, anteverted nares, a cupid
bow upper lip, low-set posteriorly rotated ears and tapering fingers.
She had hypotonia, recurrent febrile convulsions and developmental
delay . A hand radiogram showed delayed bone age . Ophthalmological
examination revealed a choroid coloboma in her left eye . Metabolic
tests and chromosomal examinations including Array-CGH analysis
with the 44k Operon chip were normal . On the basis of the general
obesity, macrocephaly, coloboma of the choroid and mental retardation
the diagnosis of MOMO syndrome was made . The comparison of
these four patients showed that a combination of obesity, macrocephaly,
ocular coloboma (especially coloboma of the retina or choroid) and
mental retardation is specific for MOMO syndrome. Due to variability
of statute anomalies we propose to form the acronym “MOMO” from
Macrocephaly, Obesity, Mental retardation and Ocular abnormalities,
excluding macrosomy from the syndrome name .
P01.324
mosaic trisomy 22: report of two patients and review of the
literature
M. Rio, S. Noel-Couillard, M. Le Merrer, M. de Blois, O. Raoul, V. Malan, A.
Munnich, M. Vekemans;
Department of genetic, paris, France.
Non-mosaic trisomy 22 is commonly seen in spontaneous abortions
and is incompatible with life . Conversely, mosaic trisomy 22 is observed
in newborns and is compatible with long survival . The clinical
presentation of mosaic trisomy 22 is variable . It includes growth retardation,
mental retardation, limb malformation, congenital heart defect
and dysmorphic features . Here we report two unrelated patients with
mosaic trisomy 22 .
Both patients were referred for genetic evaluation due to developmental
delay and failure to thrive . Patient 1 had intrauterine and post
natal growth retardation, microcephaly, complex heart defect, severe
developmental delay, facial dysmorphism, deafness, skin pigmentation
anomalies, brachydactyly, short toes with syndactyly . Interestingly,
patient 2 had an overlapping phenotype including post natal growth
retardation, non compaction of left ventricle, developmental delay,
deafness, and skin pigmentation anomalies . Facial dysmorphism,
hand and feet anomalies were also similar to the one observed in patient
1 . Routine chromosome analysis on lymphocytes showed normal
karyotype in both patients. Chromosome analysis of fibroblasts
showed a mosaic trisomy 22: 47,XY,+22[12]/46,XY [15] in patient 1,
47,XX,+22[17]/46,XX[2]. These findings were confirmed by in situ hybridization
. The phenotypic spectrum observed in both patients is compared
to previously reported cases .
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