2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
present. A heteroplasmic A8332G substitution was present in another
family, and a homoplasmic A8347C substitution in 19 cases. We
have demonstrated 5 polymorphisms and anthropologically markers
(G8251A (n=19); G8269A (n=1); C8270T (n=4); G8292A (n=8); and
a 9bp deletion (n=4). The 9bp deletion at the nt. 8271-8280 is an anthropologically
marker of East-Asian origin. The substitution C8270T
coexisted with this 9bp deletion in all cases.
Conclusion: We proved the enormous variability of the mt tRNA Lys and
the hypervariable non-coding region between COII and tRNA Lys . The
clinical symptoms developed as the result of one or more SNPs, or the
synergistic effect of its combinations. On the basis of our investigations
we suggest to start the screen for pathogenic mtDNA mutations
in tRNA Lys and tRNA Leu genes.
P02.072
metachromatic leukodystrophy, clinical course and molecular
findings; A case report of an Iranian patient
M. Akbarpour 1,2 , M. Houshmand 1 ;
1 Genetic Department of Special Medical Center, Tehran, Islamic Republic of
Iran, 2 Reproductive Medicine and Cell Science Research Center, Royan Institute,
Tehran, Islamic Republic of Iran.
Metachromatic leukodystrophy or MLD is a rare autosomal recessive
disorder of impaired breakdown of sulfatides that occur throughout the
body, but are found in greatest abundance in nervous tissue, kidneys,
and testes. The three clinical subtypes of MLD include late-infantile
MLD, comprising 50-60% of cases; juvenile MLD, comprising about
20-30%; and adult MLD, comprising about 15-20%. Age of onset within
a family is usually similar. All individuals eventually lose motor and intellectual
functions. The disease course may be from three to ten or
more years in the late infantile-onset form and up to 20 years or more
in the juvenile- and adult-onset forms. Death most commonly results
from pneumonia or other infection.
ARSA is the only gene associated with arylsulfatase A deficiency. MLD
is suggested by arylsulfatase A enzyme activity in leukocytes that is
less than 10% of normal controls using the Baum type assay. The
ARSA gene which is located on chromosome 22q13, consists of eight
exons encoding the 507 amino acid enzyme. Over 90 largely missense
mutations and polymorphisms have been identified in the ARSA gene.
The majority of mutations identified in patients with MLD are unique
within individual families.
The identity of the mutation was confirmed by amplifying all eight exons
by polymeras chain reaction which was followed by direct DNA
sequencing. The individual described in our study showed a homozygous
known missense mutation at c.1173C>G (p.T391S) in exon 7.
P02.073
Variable expression of the features of cOFs syndrome in two
sibs
E. Sukarova-Angelovska, M. Kocova, S. Spasevska, N. Angelkova;
Pediatric Clinic, Skopje, Macedonia, The Former Yugoslav Republic of.
Cerebro-oculo-facio-skeletal (COFS) syndrome is characterized by
severe microcephaly, microphtalmia, blepharophymosis, artrogryphosis
and characteristic dysmorphic face. It is a autosomal recessive degenerative
disorder with prenatal onset. Although the syndrome has
been described thirty years ago, its molecular basis has been recently
described. Defective DNA repair and homozygous mutation in the
ERCC6 gene underlies its pathogenesis.
We report on a family of unrelated parents who had two boys with
variable expression of COFS syndrome. Both pregnancies were unremarkable,
though reduced fetal growth has been noted. After the
delivery both babies serious problems for adapting to the extra uterine
life. Severity of the main signs of the syndrome was variable. Both
had microcephaly under 3rd percentile. Facial dysmorphism included
blepharophymosis, wide and nasal root, prominent philtrum, micrognatia,
large and soft ears. The first sib had more evident microphtalmia
especially of the left eye. This sib also had diastasis m. recti abdominis.
Joint stiffness was present only in small joints of the hands and feet.
The other sib had severely affected extremities with artrhrogryphisis in
all joints. Ultrasonographic evaluation has been made in both of them,
and MRI has been performed in the second, showing corpus callosum
agenesis, cerebellar hypoplasia, reduced white matter of the brain.
There are many reports of families with affected sibs having COFS
syndrome. The present clinical signs of the sibs were variable, as are
in previously described family. Although molecular diagnosis of the
syndrome has been elucidated, the reason for intrafamilial differences
is still to be evaluated.
P02.074
Use of mLPA technique for the diagnosis of particular
chromosomal abnormalities - clinical and genetic study of a
case
I. M. Ivanov 1 , C. Rusu 2 , V. Gorduza 2 , R. Popescu 2 , M. Covic 2 ;
1 Immunology and Genetics Laboratory-St Spiridon Hospital-Iasi, Romania, iasi,
Romania, 2 University of Medicine and Pharmacy “Gr.T.Popa”, Iasi, Romania,
iasi, Romania.
We present a case with multiple birth defects associated with mental
retardation due to an abnormal karyotype in order to discuss the importance
of MLPA in guiding the diagnosis.
Anamnestic data show that the infant is the only child of a young, unrelated,
apparently healthy couple. She was born after an uneventful
pregnancy, naturally, at 36 weeks, birth weight 2800g, height 48 cm,
APGAR 8. Postnatal development evolved with severe failure to thrive
and developmental delay.
Clinical examination of the child (1 year old) revealed: dysmorphic face
(tall forehead, short palpebral fissures, deep set eyes, large mouth,
large ears), short neck with excess of skin, skeletal abnormalities (congenital
hip dysplasia, bilateral talus valgus, arthrogryposis), hypotonia
and severe developmental delay.
Investigations: Echocardiography: patent ductus arteriosus, atrial
septal defect; Neurological exam: generalized muscle hypotonia, arthrogryposis;
Ophthalmologic exam: normal; Karyotype: 46 XX, add
(9)(p24); Karyotype of the parents: normal; MLPA test (with P036C and
P070 Mental Retardation Telomere Kit): triple dosage of probe DMRT1
from subtelomeric zone 9p (9p24.3). Add (9)(p24) is in fact dup9p.
Comparison of the clinical features present in our patient and those
in the literature for dup9p will be provided.In conclusion, we present
a case with a particular chromosomal abnormality in order to illustrate
a rare disorder and to discuss the use of MLPA in the identification of
chromosomal abnormalities.
P02.075
Finding genetic causes of unexplainded psychomotor
retardation cases.
B. Hernández-Charro 1 , P. Armero 1 , C. Maqueda 1 , R. Marin 2 , G. Gutierrez-Aguilar
3 , M. C. Aragón 3 , P. Madero 1 ;
1 Centro de Análisis Genéticos, Zaragoza, Spain, 2 Unidad de Genética. Hospital
Puerta del Mar, Cádiz, Spain, 3 Servicio de Pediatría. Hospital de Jerez de la
Frontera, Jerez, Spain.
Multiplex Ligation-dependent Probe Amplification (MLPA) is being routine
used to detect subtelomeric alterations in patients with idiopathic
mental retardation and other clinical features. FISH analysis, using
telomere specific probes, is performed to confirm the aberrations identified
by MLPA.
Here we present a family with three sons, two of them showing psychomotor
retardation and language difficulty, but no dismorphic features.
Parents were non consanguineous and healthy. In all of them,
kariotype was normal, at 550 level banding GTG. We performed MLPA
analysis in order to detect possible subtelomeric rearrangements, and
confirmed our results by FISH.
MLPA analysis were performed using the SALSA P069 Human Telomere
containing one probe for each subtelomeric region from chromosome
1-22 and the two X/Y pseudoautosomal regions (MRC Holland,
Amsterdam, The Netherlands). Fluorescence in situ hybridization
(FISH) with subtelomeric probes (QBiogene) were carried out.
MLPA analysis showed evidence of a deletion in the terminal region of
chromosome 3p (probe CHL1 gene in 3p26) and a duplication in the
subtelomeric region 8q (probe KIAA0150 gene in 8.q24.3) in the two
affected sons, and normal results in the other family members. FISH
using probes 3pter (D3S4558) and 8qter (D8S595) confirmed the imbalanced
subtelomeric rearrangements detected by MLPA in the affected
sons and a balanced reciprocally translocation between 3p arm
and 8q arm in the father. Mother and unaffected son were normal.
This study confirms that the combination of MLPA analysis and FISH
allows to resolve cases, where the genetic causes of the clinical features
would otherwise remain unexplained.
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