2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.049
TBX analysis in 79 Holt-Oram syndrome families reveals 80%
of genomic alterations in typical cases, 25 “new” mutations and
unusual modes of inheritance
G. de la Villeon 1 , F. Escande-Narducci 2 , A. Mezel 3 , A. Dieux-Coeslier 4 , S.
Odent 5 , A. Goldenberg 6 , S. Blesson 7 , P. Blanchet 8 , D. Martin-Coignard 9 , L. Pasquier
5 , V. Cormier-Daire 10 , B. Leheup 11 , D. Lacombe 12 , G. Morin 13 , C. Thauvin-
Robinet 14 , M. Gonzales 15 , A. David 16 , P. Jouk 17 , M. le Merrer 10 , P. Bouvagnet 18 ,
P. Makrythanasis 19 , J. Andrieux 20 , M. Holder-Espinasse 4,21 , S. Manouvrier-
Hanu 4,21 ;
1 Cardiopaediatric Department, CHRU Lille, Lille, France, 2 Molecular genetic
Department, CHRU Lille, Lille, France, 3 Paediatric orthopaedics Department,
CHRU Lille, Lille, France, 4 Clinical genetic Department, CHRU Lille, Lille,
France, 5 Genetic Department, CHU Rennes, Rennes, France, 6 Genetic Department,
CHU Rouen, Rouen, France, 7 Genetic Department, CHU Tours, Tours,
France, 8 Genetic Department, CHU Montpellier, Montpellier, France, 9 Clinical
genetic Department, CH le Mans, Le Mans, France, 10 Genetic Department,
CHU Necker, Paris, France, 11 Genetic Department, CHU Nancy, Nancy, France,
12 Genetic Department, CHU Bordeaux, Bordeaux, France, 13 Clinical genetic
Department, CHU Amiens, Amiens, France, 14 Clinical genetic Department, CHU
Dijon, Dijon, France, 15 Embryology and Genetic Department, CHU A Trousseau,
Paris, France, 16 Clinical genetic Department, CHU Nantes, Nantes, France,
17 Genetic Department, CHU Grenoble, Grenoble, France, 18 Clicardiopaediatric
Department, CHU Lyon-Bron, Bron, France, 19 Genetic Department, university
hospital Geneva, Geneva, Switzerland, 20 Genetic Department, CHRU Lille,
Lille, France, 21 Lille 2 University, Lille, France.
Holt-Oram Syndrome (HOS) is characterized by the association of upper
limb radial-ray and heart malformations. The transmission is autosomal
dominant and TBX5 mutations are observed in about 75%
of the typical patients, so that genetic heterogeneity is likely. SALL4
mutations are responsible for some atypical cases.
79 families (126 patients) were referred for TBX5 analysis. Using precise
diagnostic criteria we classified them in two separate groups: 46
(91 patients) were considered “typical” and 33 (35 patients) were considered
“atypical”.
Sequencing of exonic and intronic flanking regions of TBX5, as well
as QMPSF and MLPA were performed. Thirty-seven anomalies (80%)
were identified in the typical families (13 nonsense, 10 frameshift, 7
point, and 3 splice mutations; 3 exonic deletions, 1 exonic duplication).
To our knowledge 25 of these 37 anomalies had never been reported
previously. Variable clinical expression is the rule in HOS and was
confirmed in our patients. Important intrafamilial variability was also
noticed in one family (slight abnormal clavicle curvature in a mother
and very severe radial ray defects in her two daughters). Somatic mosaicism
was identified in one asymptomatic case.
In the 33 “atypical families”, a precise diagnosis could be performed
in 9/33 (27%). A TBX3-TBX5 deletion in a patient presenting features
of both HOS and Ulnar-mammary syndrome was identified. In the 32
remaining families, a diagnosis was achieved in 8 cases (1 Fanconi, 1
Okihiro, 1 TAR, 2 fetal valproate syndromes, and 3 array-CGH anomalies).
This large series highlights genetic heterogeneity and clinical variability
in HOS.
P02.050
clinicopathological pattern and genetic mapping of fetal
cerebral proliferative vasculopathy: the Fowler syndome
F. Encha-Razavi 1,2 , B. Bessières 3 , N. Leticee 4 , S. Zerelli 1 , M. Bonnière 5 , P.
Marcorelles 6 , A. Laquerrière 7 , J. Martinovic 2 , V. Cayol 3 , C. Fallet 8 , B. Foliguet 9 ,
M. Vekemans 1,2 , T. Attie-Bitach 1,2 ;
1 INSERM U781, Paris, France, 2 Hopital Necker, APHP, Paris, France, 3 Institut
de Puériculture, Paris, France, 4 Maternité, Hôpital Necker, Paris, France,
5 Anatomopathologie, Lille, France, 6 Anatomopatholgie, Brest, France, 7 Anatomopathologie,
Rouen, France, 8 Hôpital Sainte-Anne, Paris, France, 9 Anatomopatholgie,
Nancy, France.
Cerebral proliferative glomeruloid vasculopathy (CPGV) is a severe
disorder of central nervous system (CNS) angiogenesis, resulting in
abnormally thickened and aberrant perforating vessels, forming glomeruloids
with inclusion bearing endothelial cells. This peculiar vascular
malformation was delineated by Fowler in 1972 in relation with
a familial, lethal, fetal phenotype associating hydranencephaly-hydrocephaly
with limbs deformities, called proliferative vasculopathy and
hydranencephaly-hydrocephaly (PVHH). Our clinicopathological study
in a series of 14 fetuses from 8 unrelated families, permits identification
of a diffuse form of PGV, affecting totally the CNS that we opposed
to focal forms, confined to restricted territories of CNS.
In PVHH, the disruptive impact of vascular malformation on the developing
CNS is now well admitted. However, the mechanism of abnormal
angiogenesis involving exclusively brain vasculature remains unknown.
Recurrences and consanguinity have been reported, suggesting
autosomal recessive inheritance.Among the 8 families we report, 3
are consanguineous with 2 affected sibs in each. A genome wide scan
with Affymetrix SNP 250K is currently being performed in these 3 families,
and will hopefully point to the Fowler syndrome locus.
P02.051
A new phenotype in a family with inability of tongue movement,
dysmorphic face, hypernasal speech, hypogonadism and
syndactyly.
A. Yesilyurt 1 , S. Kozan 1 , D. Torun 1 , M. Bahce 1 , A. Koc 1 , &. Demirkaya 2 , G.
Genc 2 , &. Güran 1 ;
1 Gülhane Military Medical Academy, Department of Medical Genetics, Ankara,
Turkey, 2 Gülhane Military Medical Academy, Department of Neurology, Ankara,
Turkey.
Dysmorphic face with microbrachycephaly, triangular and elongated
face, fine hair, frontal upsweep, narrow forehead, bitemporal narrowing,
thick and medially-flared eyebrows, prominent tubular nose, prominent
columella, enophtalmus, thin lips, pointed chin findings may be
related any type of a dysmorphic syndromes. Inability of tongue movement,
hyper nasal speech, hypogonadism and syndactyly in addition
to dysmorphic face findings in two affected cases in a consanguineous
family may represent a new type of rare phenotype with autosomal recessive
inheritance pattern. Here we presented a male patient which is
characteristic with the limitation of tongue movement, and dysmorphic
face, hypogonadism and syndactyly findings. He had 46,XY karyotype.
His sister had similar clinical findings including dysmorphic face and
limitation of tongue movement except syndactyly. We have not performed
her hormonal analyses for the observation of hypogonadism
yet. Interestingly, no EMG abnormality was detected in tongue and
whole body muscles. There was no cardiac and brain defect according
to ECHO cardiography and cranial tomography results, respectively.
So limitation of tongue movement and other abnormalities in a consanguineous
family seems as a new phenotype with autosomal recessive
inheritance pattern.
P02.052
isolated Hereditary Hypotrichosis Research in Russia
E. I. Sharonova 1 , N. V. Petrova 1 , K. N. Suvorova 2 , E. D. Nefedova 2 , A. V. Arbukova
1 , R. A. Zinchenko 1 ;
1 Research Centre for Medical Genetics, Russian Academy of Medical Sciences,
Moscow, Russian Federation, 2 Russian Medical Academy of Postgraduate
education, course of the skin and veneral disorders in childhood, Moscow,
Russian Federation.
Laboratory of Genetic Epidemiology RAMS in collaboration with course
of the skin and veneral disorders in childhood of Russian Medical
Academy of Postgraduate education study hair growth abnormalities
and scalp hair loss. In collaboration with Rogaev E.I., in 2006 year we
mapped phospholipase gene (LIPH) from identified by us 59 Mari and
Chuvash families, which had isolated hereditary hypotrichosis, and
described mutation - deletion of exon 4 of the LIPH gene. We studied
frequency of this mutation in healthy individuals of different ethnosis
from the Volga-Ural region: Maris, Chuvashs, Bashkirs, Udmurts and
Russian. At this moment, we found new mutation in P2PY5 receptor
gene in one patient who had the similar to isolated hereditary hypotrichosis,
caused by deletion of exon 4 of the LIPH gene, phenotype and
hair structure. Further, we examined one family with clinical presentation
similar to hereditary hypotrichosis, but in this family we observed
spontaneously symptoms regress in adult age (although symptoms
did not disappear completely). Hairs show typical beaded or monilethrix
appearance and elliptical nodes separated by narrow internodes
without medullary layer. We examined the patient with monilethrix by
means of molecular genetic tests. We detect previously known mutation
in 7 exon of the hHb6 gene. So, clinical presentation of hair growth
abnormalities is similar in different gene defects. As a result, now we
are working out the differential-diagnostic criteria for genetically different
forms of isolated hereditary hypotrichosis.