2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
had Brugada Syn and some had LQT3 .we checked SCN5a and we
can fined KPQ del 1505-1507 in all pationts.As you know this del was
caused only LQT3.so it was very interesting that we can find this del in
Brugada syndrome . So we are working in other hypothesis for solving
this situation
P05.178
seckel-syndrome like phenotype associated with a 550 kb
microdeletion of the long arm of chromosome 5 characterized by
array comparative genome hybridization (acGH)
P. M. Kroisel1 , A. C. Obenauf1 , B. Plecko2 , K. Wagner1 , M. R. Speicher1 , T.
Schwarzbraun1 ;
1 2 Institute of Human Genetics, Graz, Austria, Department of Pediatrics, Graz,
Austria.
Primordial dwarfism and Seckel-syndrome are rare genetically heterogeneous
disorders . Several subtypes of these severe growth retardation
syndromes have been described mainly based on clinical
features, growth characteristics, presence or absence of particular
skeletal anomalies and further criteria . During the last years a remarkable
progress in identification of genes involved was achieved. Seckelsyndrome
and primordial dwarfism can be genetically caused following
an autosomal recessive mode of inheritance . Genes involved in cell
division, cell cycle control pathways or related to DNA repair have recently
been identified and characterized to be responsible for some
forms of these disorders when a homozygous loss of function mutation
is present . Here we report on a 3 ½ year old male patient resembling
phenotype features of Seckel-syndrome associated with a 550 kb microdeletion
5q33 detected by high resolution aCGH . The patient is the
fifth child of young healthy non-consanguineous parents. Birth weight
was 800 g, length 37 cm . No precise information about gestational
week at birth was available . Weight at 3 ½ years is 4 .450 g, length 62 .4
cm and head circumference 39 .8 cm . He shows a beaked nose, low
set ears, micro- and retrognathia, transverse palmar creases, fifth finger
clinodactyly, general hirsutism and darker skin pigmentation than
relatives . Psychomotor development is good, however he is unable
to speak because he has a tracheostoma since more than two years .
Investigation of those less than 20 genes deleted and the molecular
rearrangement could allow identifying a gene responsible for a variant
form of primordial dwarfism or Seckel syndrome.
P05.179
Severe Combined Immunodeficiency (SCID) caused by R235Q
homozygous mutation in adenosine deaminase (ADA) gene
F. Mora, J. F. Rodríguez-Gutiérrez, M. Bernal, J. A. Brieva, A. Nieto, A. Sampalo;
Hospital Puerta del Mar, Cádiz, Spain.
Inherited deficiency of ADA accounts for approximately 17% of SCID
and 50% of autosomal recessive SCID .
Patient: a two months old boy from Morocco with a suspection of SCID
(severe infections, diarrhea, failure to thrive, profound lymphopenia) .
Parents were consanguineous (first cousins). Erythrocyte ADA enzyme
activity was assayed: ADA activity in patient was nearly indetectable
while in his parents it was about 50% of a control . In his healthy
brother activity was normal .
Molecular diagnosis: nearly 70 different mutations have been described
in ADA gene causing SCID; half of them are “private” . Most
patients are heteroallelic and homozygosity is mostly restricted to consanguineous
families .
Mutational analysis of ADA gene was performed . We designed primers
for PCR amplification of the 12 exons comprising the gene. PCR
products were purified and sequenced with the amplification primers
using BigDye Terminator Cycle Sequencing kit in an ABI 310 Genetic
Analyzer .
Results: The patient was homozyguos for R235Q (704G>A) missense
mutation in exon 8 . Both parents were heterozygous for this mutation .
His healthy brother was also heterozygous, in spite of his normal ADA
activity. It is the first time that R235Q mutation is detected in homozygosity
in a SCID patient, and the first time this mutation is detected
outside of Japan .
Patient was also homozygous for D8N (22G>A) polymorphism in exon
1; parents and brother were carriers . This polymorphism is not related
to SCID but it causes decreased enzyme activity and can contribute to
the low level of ADA activity in the patient .
P05.180
mutations in SHOX do not appear to be involved in Léri-Weill
dyschondrosteosis (LWD) and idiopathic short stature (iss)
M. Aza-Carmona 1 , D. Gorbenko del Blanco 1 , S. Benito-Sanz 1 , P. Lapunzina 2,3 ,
J. Argente 1,4 , K. E. Heath 1 ;
1 Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid,
Madrid, Spain, 2 Hospital Universitario La Paz, Universidad Autónoma de Madrid,
Madrid, Spain, 3 CIBERER Instituto de Salud Carlos III, Madrid, Spain,
4 CIBER (CB06/03) Instituto de Salud Carlos III, Madrid, Spain.
SHOX encodes a transcription factor involved in determining stature in
humans . Mutations/deletions of SHOX and a downstream region result
in Léri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia
and idiopathic short stature (ISS) . However, no molecular defect has
been detected in a variable proportion of LWD/ISS cases . SHOX has
a human homolog, SHOX2, located on chromosome 3q25 .32, which
function is unknown . The Shox2-/- mouse presents a cleft palate phenotype
with shortened limbs, suggesting that SHOX2 may participate
in limb development .
In order to investigate if SHOX2 is implicated in LWD/ISS, we have
analyzed 35 LWD/ISS families and 89 ISS individuals, without a known
molecular defect . SHOX2 mutation screening was performed by dH-
PLC and DNA sequencing of the exons and intron/exon boundaries .
Large deletions were analyzed in the familial cases using previously
described (D3S3692) and novel microsatellites (D3S4638, D3S4639
and D3S4640) flanking SHOX2 .
Two variants were identified in exon 1 of SHOX2 in two familial cases:
a missense mutation E21K and a duplication of three glycines Gly77-
Gly78dup (c .232_233dupGAGGAGGTG) . We subsequently screened
exon 1 in 50 healthy individuals . The E21K mutation was not observed
in controls but it did not cosegregate with the short stature phenotype .
Insertions and deletions of the glycine repeat in SHOX have been described
in patients with LWD/ISS but the insertion in the glycine repeat
of SHOX2 appears to be polymorphic as we observed duplications of
this region in three normal controls .
These results suggest that SHOX2 is not the molecular cause of the
LWD/ISS in the cases studied .
P05.181
Pathways of sOD1 and tAU-induced motor neuron degeneration
L. C. Kudo, L. Parfenova, J. Pomakian, H. V. Vinters, M. Wiedau-Pazos, S.
Karsten;
David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative
disease that selectively affects motor neurons . To identify early
molecular triggers of selective motor neuron degeneration, we applied
microarray technology to investigate gene expression profiles
of motor neurons and glia isolated with laser capture microdissection
from two distinct transgenic mouse models of ALS: SOD1-G93A and
TAU-P301L . The analysis was performed prior to the development of
neurodegeneration reducing the number of false positives due to the
possible reactive changes in the course of the disease . The majority of
identified genes are model specific, indicating that TAU and SOD1 induced
neurodegeneration have distinct molecular pathways and therefore,
may require specific treatments. Several genes were consistently
altered in the motor neurons of both models . One of them, Dynein,
points to the early dysfunction of retrograde axonal transport . To investigate
the relevance of microarray identified gene expression changes
for human sporadic disease, immunohistochemical experiments were
carried out using a specific ALS tissue microarray (TMA) consisting of
ALS, FTD and control human postmortem CNS tissues .
P05.182
Alu-related 5q35 microdeletions in sotos syndrome
N. Matsumoto 1 , J. Mochizuki 1,2 ;
1 Department of Human Genetics, Yokohama City University Graduate School of
Medicine, Yokohama, Japan, 2 Department of Obstetrics and Gynecology, Kitasato
University School of Medicne, Sagamihara, Japan.
Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or
intragenic mutations causes Sotos syndrome (SoS) . In 46 of the 49
Japanese deletion-cases, common deletion breakpoints were located
at two flanking low copy repeats (LCRs), implying that non-allelic homologous
recombination (NAHR) between LCRs is the major mechanism
for the common deletion . In the remaining three cases of atypical