2008 Barcelona - European Society of Human Genetics

Clinical genetics
were assumed to be at risk for UPD . To date, only one case with abnormal
karyotype involving maternal UPD16 was reported as body stalk
anomaly [Chan et al ., 2000] . Although the parental origin of normal 16
and der(16) remained to be determined, this case will provide insight
into consideration of pathogenetic mechanism of sirenomelia .
P01.360
Hereditary spastic paraplegia, type 4, in Russian families
G. E. Rudenskaya, I. S. Sermyagina, A. Kalygina, S. Kazakova, A. V.
Polyakov;
Research Centre for Medical Genetics, Moscow, Russian Federation.
Hereditary spastic paraplegia (HSP), type 4, or SPG4, caused by
various mutations in spastin gene (SPAST) is the most common disorder
in a heterogeneous group of autosomal dominant HSP’s . We
performed a search of SPAST mutations by routine methods (SSCP
and subsequent direct sequencing of fragments with modified electrophoretic
mobility) in a sample of 26 families with autosomal dominant
HSP from different Russian regions. In six families, five of Russian and
one of Tatar ethnicity, different SPAST mutations were detected . Three
of them, Arg431Stop, 839-840 delAG, and Asn386Ser, were already
reported; the remaining three, Asp555Tyr, 1107A>G, and Asn184Thr,
were novel . One more large family showed a linkage to SPG4 locus
(lod score 1 .51) but mutation was not found . This may be due to atypical
SPAST mutations (partial deletions etc) undetectable by routine
methods of DNA analysis . Including this family, the proportion of SPG4
in the sample is 27%, which is less than average world data (40_50%) .
Most of our patients presented relatively late-onset “uncompicated”
HSP, which is typical for SPG4 . Though, in some families additional
features were reported, epilepsy among them . One of our patients had
very early-onset HSP and concomitant epilepsy while his mother had
typical SPG4 presentation . All pedigrees showed complete penetrance
though some patients, women particularly, had mild signs of the disease,
even late in life . Another relatively frequent autosomal dominant
HSP is SPG3 caused by mutations of atlastin gene (6_10%) . We plan
to perform a search of atlastin mutation in families without SPAST mutations
.
P01.361
Glaucoma, short stature, mental retardation and ischemic
stroke: A new autosomal-recessive syndrome mapping to
chromosome 20q11-12
F. Rutsch1 , C. George1 , M. Frosch1 , C. Becker2 , G. Nürnberg2 , P. Nürnberg2 ;
1 2 University Children’s Hospital, Muenster, Germany, Cologne Center for Genomics,
Cologne, Germany.
We report on a family with multiple affected siblings of both sexes presenting
with a novel combination of anomalies including cerebrovascular
insults .The four affected probands were born to consanguineous
Turkish parents, there are six non-affected siblings . All four probands
have a short stature . The eldest male had congenital left sided glaucoma,
presented with a stroke at the age of 6 months and showed a
severe developmental delay . He died at 40 years of age . The second
proband suffered from right-sided congenital glaucoma and recurrent
strokes starting at the age of one year . He was wheel-chair dependent
and developed multiple joint contractions . He died of an intracranial
hemorrhage at the age of 28 years . The third proband had bilateral
congenital glaucoma . She is only mildly developmentally retarded, but
also developed multiple joint contractions . The youngest proband also
suffers from congenital left sided glaucoma and severe developmental
delay . She was never able to walk and showed precocious puberty .
At the age of 14 years, she had an ischemic stroke of the left arteria
cerebri media . MRI angiography showed total occlusion of the internal
carotid arteries bilaterally and of the left arteria cerebri media . Homozygosity
mapping in this family, using a high density SNP array, identified
a candidate locus of 7.3cM on chromosome 20q11-12. The familial
association of congenital glaucoma, mental retardation, short stature
and ischemic stroke is a hitherto unreported entity . This autosomal-recessive
syndrome is mapping to chromosome 20q11-12 .
P01.362
screening of telomeric regions by mLPA in more than 470
patients with mental retardation and fetuses with malformations
R. L. Touraine1 , A. Combes1 , M. Gilet1 , M. Till2 , D. Sanlaville2 , P. Edery2 , P.
Jouk3 , V. Herbepin-Granados1 , F. Prieur1 ;
1 2 CHU de Saint Etienne, Saint etienne, France, CHU de Lyon, Lyon, France,
3CHU de Grenoble, Grenoble, France.
Cryptic telomeric rearrangements are frequent causes of mental retardation
and/or malformation syndromes . We used for more than 2
years, a systematic screening of all subtelomeric regions using MLPA
with two commercial kits from MRC Holland .
We studied more than 470 patients, including 44 fetuses with malformations
. Except for theses fetuses, all the patients had mental retardation,
associated for most of them with some malformation or dysmorphic
features . In every cases, but four, standard karyotype analysis
was normal .
Only one fetus (2,5 %) is probably positive . This case is likely a 15q
deletion, but FISH analysis was not possible to confirm it.
Among our postnatal cases, 15 anomalies, not suspected on karyotype
analysis were confirmed (3,5%) and 4 suspected anomalies were
further analyzed .
In addition some anomalies with only one MLPA kit were identified in
an unaffected parent and therefore considered as polymorphism . On
the opposite, true anomalies were sometimes detected with only one
MLPA kit .
Unexpectedly, 5 anomalies implied M9p, including 3 «pure» subtelomeric
monosomies . One case was familial, inherited from the mother
(with border-line mental retardation) .
In conclusion, MLPA technique for telomeric screening is interesting
and not very expensive . Furthermore, some of the anomalies we detected
here, were almost «non-syndromic», favoring a non-specific alltelomeres
screening approach in mental retardation .
At last, further molecular analysis, including CGH-array, of our M9pter
cases is in progress to refine phenotype/genotype correlations.
P01.363
testicular dysgenesis syndrome: more common after assisted
reproduction?
S. Funke, E. Flach, Z. Mánfai, T. Ertl;
University of Pécs, Pécs, Hungary.
Recent reports have demonstrated a decline in human male reproduction
health: increasing prevalence of cryptorchidism, hypospadias, poor
semen quality, rising incidence of testis cancer and growing demand
for assisted reproduction . It is supposed that these are symptoms of
one underlying entity, the testicular dysgenesis syndrome (TDS) . The
rapid rise in the prevalence of TDS may be linked to endocrine disrupters
affecting genetically susceptible individuals . Genetic aberrations
or polymorphisms may predispose to augmented effects by environmental
factors . Meta-analysis of in vitro fertilization (IVF) studies revealed
that hypospadias is more common after assisted reproduction
(AR) . In Hungary about 2000 infants are born following IVF yearly . In
our study we investigated the incidence of congenital abnormalities
after AR . At the Department of Obstetric and Gynaecology, Medical
School, University of Pécs 712 newborn infants were born after IVF
between January 1 st , 1999 and December 31 th , 2006, 319 singletons
and 178 sets of twins . The mean gestational age was 35 .6±2 .1 weeks,
the mean birthweight 2520±630 grams . The incidence of congenital
abnormalities in infants born after conventional IVF was compared to
newborns born after intracytoplasmatic sperm injection (ICSI) . In regard
to major congenital abnormalities we did not find any significant
differences between the two groups (5 .8% vs 3 .2%, p=0 .056) . Infants
born after ICSI significantly more often suffered from minor anomalies
[p=0 .004, OR:1,9478 (95%CI:1 .1916-3 .1841)], especially from genital
abnormalities, hypospadias, cryptorchidism, hydrocele testis [p=0 .031,
OR:2,48 (95% CI:0 .9949-6 .1594)] . Further investigations will be needed
to confirm the supposition that children born after IVF/ICSI are at
higher risk to develop TDS .