European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
P0054. Population investigation of alpha-1-antitypsin in some
regions of the Azerbaijan Republic
A. B. Ismayilova;
Baku State University, Baku, Azerbaijan.
Alpha-1-antitrypsin (α1A) is low molecular protease inhibitor, synthesized
by liver cells, which destroys neutrophil elastase of lung alveolar
cells. So far, 90 mutant and normal alleles of the α1A gene are
known.
In our researches we have identified α1A phenotypes in healthy persons
as well as in patients with lung and liver disease. Capillary blood
(0,2 ml) with anticoagulation agent-heparin was collected in eppendorf
tubes. Two regions of Azerbaijan Republic (Siyazan and Kazakh)
were involved in population studies. Siyazan area is located 110 km
northward and Qazakh area 450 km west-northward from Baku city.
Altogether 897 person’s blood samples were screened.
Phenotype testing was carried out by isoelectric focusing (IEF) in thin
layer polyacrylamide- ampholine gels (PAAG), pH 4-6.
Three normal phenotypes of PiM alleles were identified in homozygous
as well as in compound state with frequencies of: M1M2- 32%,
M1M3-20% and M2M3-12%. The frequency of PiM alleles was : M1-
38%,M2-38% and M3-24%.
In six families two types of mutations were defined as with PiZ (6 persons)
and PiS (4 persons).
IEF method in PAG with pH 4-6 is recommended for identifying phenotypes
of alpha-1-antitrypsin in population studies.
P0055. Microstomia- cleft palate: a new syndrome?
S. A. Boyadjiev 1 , R. Saadeh 2 , A. Scott 2 , W. Tian 3 , A. Mian 3 , E. Wulfsberg 3 , T.
Beaty 4 , C. Vander Kolk 5 , R. Redett 5 ;
1 Section of Genetics, Sacramento, CA, United States, 2 McKusick-Nathans Institute
of Genetic Medicine, The Johns Hopkins University School of Medicine,
Baltimore, MD, United States, 3 Department of Pediatrics, University of Maryland,
Baltimore, MD, United States, 4 Department of Epidemiology, The Johns
Hopkins University School of Public Health, Baltimore, MD, United States, 5 Department
of Surgery, Division of Plastic Surgery, The Johns Hopkins University
School of Medicine, Baltimore, MD, United States.
The unusual combination of extremely small mouth with U-cleft palate
was observed in two unrelated families. While mild micrognatia was
described in infancy, it was not obvious in later life. In fact, prominent
and pointed chin was present in the affected adults. In the first family,
a mother and her daughter had these oral anomalies and downslanting
palpebral fisssures. No associated birth defects or delays were
present. In the second family, the affected mother had a son and fraternal
twin daughters with the same combination of oral features and
brachydactyly and 5 th finger clinodactyly. In addition to the oral defects,
the youngest boy in this family had craniosynostosis and ureteral obstruction
resulting in chronic renal failure. Whole-genome genotyping
with Illumina 317K SNP Beadchip did not detect chromosomal rearrangements.
The diagnosis of Pierre Robin sequence was considered
unlikely based on the clinical presentation and extracranial dysmorphisms.
More than 50 syndromes featuring microstomia and cleft
palate were reviewed and excluded. We propose that this condition
represents a new autosomal dominant dysmorphic syndrome. Linkage
analysis of these and additional families with similar features is likely
to pinpoint the location of a gene essential for proper development of
the oral region.
P0056. Novel missense mutation: R131C in the RUNX2 gene in a
case with cleidocranial dysplasia
V. Belengeanu 1 , D. Steinberger 2 , S. Farcaş 1 , C. Popa 1 , K. Rozsnyai 1 , D. C.
Bratu 3 ;
1 Department of Medical Genetics, University of Medicine and Pharmacy,
Timişoara, Romania, 2 Bioscientia Center for Human Genetics, Ingelheim,
Germany, 3 Department of Orthodontics, University of Medicine and Pharmacy,
Timişoara, Romania.
Cleidocranial dysplasia is a skeletal dysplasia characterized by persistently
open or delayed closure of sutures, hypoplastic and/or aplastic
clavicles, wide pubic symphysis, dental anomalies, and short stature.
The disorder is caused by heterozygous mutations in the CBFA
(core binding factor alpha1) gene, also known as RUNX2 (runt-related
gene 2) on chromosome 6p21, that encodes an osteoblast-specific
transcription factor. Mutations scattered throughout the entire CBFA1
gene have been related to this disorder, however, most of them affect
the highly conserved Runt domain, abolishing the DNA-binding ability
of the transcription factor. We report a case presenting with the classic
phenotype of cleidocranial dysplasia, in which mutation analysis of
the RUNX2 gene revealed a previously unreported missense mutation
(391C>T), that replaces an arginine residue with a cysteine at position
131, in the Runt homology domain of the RUNX2 protein. The mutation
occurred the novo, neither of the parents, who were phenotypically
normal, carried the mutation identified in the patient. We describe our
detailed investigation of the patient, expanding the data related to the
phenotypic expression of different mutations in the RUNX2 gene.
P0057. Further Expansion of the Behavioral and
Neurodevelopmental Phenotypic Prensentation of Boys with 49
XXXXY ( A variant of XXY)
C. A. Samango-Sprouse 1 , A. Gropman 1 , S. A. Rosenson 2 , A. Rogol 3 ;
1 George Washington University, Washington, DC, United States, 2 University
of Texas, Austin, TX, United States, 3 University of Virginia, Charlottsville, VA,
United States.
This is a comprehensive study completed on a large cohort of boys
with 49 XXXXY (49XY) describing intact nonverbal IQ and receptive
comprehension skills with severe developmental dyspraxia. 15 boys
were evaluated using standardized measures by a multi-disciplinary
team including pediatric neurology, genetics, endocrinolgy, development,
physical therapy and speech/language.
The mean age of the cohort was 37 months with mean birth weight of
5lbs. 7ozs. The average age at the time of diagnosis was 4 mos. Mean
Nonverbal IQ was 92 with receptive comprehension standard scores
of 81.7 in contrast to depressed verbal capacities with standard scores
of 66.5. There was severe motor praxis deficits with global hypotonia in
all children. Sensory integration dysfunction was evident.
These findings describe for the first time intact nonverbal skills and
comprehension with severe motor planning deficits in boys with this
rare disorder. This study expands the phenotypic presentation of 49
XY to include better nonverbal IQ capacities than appreciated previously.
Speech is severely delayed secondary to verbal and oral motor
dyspraxia. The presence of limb dyspraxia affects graphomotor
function. Behavioral issues were evident in some but not all children.
These finding support evidence of frontal lobe dysfunction as previously
demonstrated in boys with XXY.
Counseling for newly diagnosed families needs to highlight variability
of intellectual capabilities, the need for aggressive EI services with direct
SPL and OT for motor planning deficits. Further studies are underway
to further investigate phenotypic variability, MRI abnormalities and
the presence of mosiacism in the higher functioning children.
P0058. Cockayne Syndrome Type II: a unique phenotype
among Druze Population in Northern Israel Caused by a Highly
Prevalent Novel Mutation in the CSB Gene.
T. C. Falik-Zaccai1,2 , M. Laskar1 , N. Kfir1 , W. Nasser3 , H. Slor4 , M. Khayt1 ;
1 2 Istitute of Medical genetics, Western Galilee Hospital, Naharia, Israel, Rappaport
Faculty of Medicine, Technion- Israel Institue of Technology, Haifa, Israel,
3Department of Pediatric Nephrology, Western Galilee Hospital, Naharia, Israel,
4Department of Human Molecular Genetics and Biochemistry, Sackler School of
Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Cockayne Syndrome (CS) (OMIM # 216400) is a rare autosomal recessive
disease characterized by severe growth and developmental
retardation, progressive neurological dysfunction and symptoms of
premature aging. The primary cause of the disease is a defect in the
transcription-coupled DNA repair, specifically the Nucleotide Excision
Repair (NER) pathway. To date, four genes along this pathway CS-
A, CS-B, XP-D and XP-G have been reported to be involved in the
pathogenesis of CS.
We have identified a large, highly consanguineous, Druze kindred
descended from a single ancestor, with six CS patients. All patients
presented with congenital severe phenotype that includes severe failure
to thrive, severe mental retardation, congenital cataracts, loss of
adipose tissue, joint contractures, bird-like faces with small, deep-set
eyes and prominent nasal bridge, and kyphosis. All patients exhibited
neither language skills nor independent sitting or walking and died by
the age of 5 years.
Cellular studies in patients‘ fibroblasts showed significant defect in
transcription-coupled DNA repair (TCR) and a marked correction of
the abnormal cellular phenotype with a plasmid containing the cDNA