2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
2-2.2 Mb. This deletion, which encompasses several genes including
RPGR, OTC, TSPAN7 and BCOR, was also present in the mother and
the sister of the proband. Both of them also have congenital cataract
and dental anomalies, and hammer toes as well as bilateral 2-3 toe
syndactyly were also present in the sister.
Among the deleted genes, TSPAN7 plays a role in mental retardation,
and BCOR (BCL6 co-repressor) seems to be the best candidate gene
to explain the familial clinical features. Several frameshift, deletion,
nonsense mutations and exonic deletions were found in BCOR causing
Oculo-facio-cardio-dental (OFCD) syndrome. OFCD syndrome is
an X-linked dominant condition with presumed male lethality characterized
by multiple congenital anomalies: cardiac abnormalities (septal
defects), ocular malformations (congenital cataracts, microphtalmia),
facial dysmorphic features, cleft palate and dental anomalies (delayed
dentition, oligodontia, abnormal shaped teeth, radiculomegaly). Some
reported cases developed psychomotor and mental retardation.
P02.085
Renal insufficiency, a frequent complication of oral-facial-digital
syndrome type i
S. Saal 1,2 , L. Faivre 1,2 , B. Franco 3 , A. Toutain 4 , L. Van Maldergem 5 , A. Destrée 5 ,
I. Maystadt 5 , P. S. Jouk 6 , B. Loeys 7 , D. Chauveau 8 , E. Bieth 9 , V. Layet 10 , M.
Mathieu 11,12 , J. Lespinasse 13 , N. Gigot 14 , B. Aral 14 , E. Gautier 15 , C. Binquet 15 , A.
Masurel-Paulet 1,2 , C. Mousson 16 , F. Huet 17 , C. Thauvin-Robinet 1,2 ;
1 Centre de Génétique, Hôpital d’Enfants, C.H.U. Dijon, France, 2 Centre de
Référence Maladies Rares -Anomalies du Développement Embryonnaire et
Syndromes Malformatifs- de la Région Grand Est, France, 3 Laboratorio di
Ricerca, Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy,
4 Service de Génétique, C.H.U. Tours, France, 5 Institut de Pathologie et de Génétique,
Loverval, Belgium, 6 Service de Génétique, C.H.U. Grenoble, France,
7 Centre de Génétique Médicale, Ghent, Belgium, 8 Service de Néphrologie - Immunologie
Clinique, C.H.U. Hôpital Rangueil, Toulouse, France, 9 Laboratoire
de Génétique, C.H.U. Purpan, Toulouse, France, 10 Unité de Cytogénétique et
Génétique médicale, C.H. Le Havre, France, 11 Département de Pédiatrie - Unité
de Génétique Clinique, C.H.U. Hôpital Nord, Amiens, France, 12 Centre de Référence
Anomalies du Développement et Syndromes Malformatifs de la Région
Nord, France, 13 Laboratoire de Génétique Chromosomique, C.H. Chambéry,
France, 14 Laboratoire de Génétique Moléculaire, Hôpital du Bocage, C.H.U.
Dijon, France, 15 Inserm, CIE1, Centre d’Investigation Clinique - Epidémiologie
Clinique/Essais Cliniques, Dijon, France, 16 Service de Néphrologie, Hôpital
du Bocage, C.H.U. Dijon, France, 17 Service de Pédiatrie 1, Hôpital d’Enfants,
C.H.U. Dijon, France.
The oral-facial-digital syndrome type I (OFDI) involves multiple congenital
malformations of the face, oral cavity and digits. It is the most
frequent type of oral-facial-digital syndrome, characterised by X-linked
dominant mode of inheritance with lethality in males. The OFD1 gene
encodes for a centrosomal protein located both in the primary cilium
and in the nucleus, leading to consider the OFDI syndrome as a ciliopathy.
A polycystic kidney disease (PKD) is reported in almost one third
of OFDI patients, but long-term outcome of the renal disease has been
essentially described through isolated cases. We report on the renal
manifestations of a cohort of 34 patients with an identified mutation
in the OFD1 gene. Patients are aged of 1 to 68 years. Their median
follow-up is of 16.5 years. Among them, 12 (35%) patients presented
with PKD (11/16 (69%) if only adults were considered) with a median
age at discovery of 29 years. Ten of them also presented with renal
impairment and six were grafted. One grafted patient under immunosuppressive
treatment died from a malignant tumor originated from a
native kidney. In patients aged 36 or more, the probability to develop
renal failure was estimated to be more than 50%. Besides, neither
genotype-phenotype correlation nor clinical predictive association with
renal failure could be evidenced. These data reveal an unsuspected
high frequency with age of renal impairment in OFDI syndrome. Systematic
ultrasound scans and renal function follow-up are therefore
highly recommended for all OFDI patients.
P02.086
mutational spectrum of the Oral-facial-digital type i syndrome: a
study on a large collection of patients
B. Franco 1,2 , C. Prattichizzo 1 , M. Macca 1,2 , V. Novelli 1,2 , R. Tammaro 1 , G. Giorgio
1 , A. Barra 1 , The OFDI collaborative group;
1 Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy, 2 Department
of Pediatrics, University Federico II, Naples, Italy.
Oral-facial-digital type I (OFDI; MIM 311200) syndrome is a male lethal
X-linked dominant developmental disorder belonging to the heterogeneous
group of Oral-facial-digital syndromes (OFDS). OFD type I is
characterized by malformations of the face, oral cavity and digits. CNS
abnormalities and cystic kidney disease can also be part of this condition.
This rare genetic disorder is due to mutations in the OFD1 gene
that encodes a centrosome/basal body protein necessary for primary
cilium assembly and for left-right axis determination, thus ascribing
OFDI to the growing number of disorders associated to ciliary dysfunction.
We now report a mutation analysis study in a cohort of 109 unrelated
affected individuals collected worldwide. Putative disease-causing
mutations were identified in about 80% of patients. We describe
67 different mutations, 64 of which are novel, including 36 frameshift,
9 missense, 11 splice-site and 11 nonsense mutations. Most of them
concentrate in exons 3, 8, 9,12,13 and 16, suggesting that these may
represent mutational hotspots. Phenotypic characterization of the patients
collected provided a better definition of the clinical features of
OFD type I. Differently to what previously observed, our results indicate
that renal cystic disease is present in 60% of cases with over 18
years of age. Genotype-phenotype correlation reveal significant associations
of the high-arched/cleft palate most frequently associated to
missense and splice-site mutations. Our results contribute to expand
our knowledge on the molecular basis of OFD type I syndrome. In
addition these results will help in defining the clinical spectrum and
recognition of Oral-facial-digital syndromes.
P02.087
isolated oligodontia and hypodontia in multiplex families
E. Severin, C. C. Albu, D. F. Albu, D. Stanciu;
“Carol Davila” Univ Med Pharm, Bucharest, Romania.
Introduction: Oligodontia is defined as congenital lack of more than
six teeth and hypodontia is used when one to six teeth are missing.
Oligodontia is a rare anomaly of tooth number while hypodontia is a
common one. Both anomalies have a genetic background and are inherited
in successive generations of a family.
Objectives: to evaluate and compare the pattern of missing teeth in
families, to observe similarities and differences of dental phenotype
among affected relatives, to characterize the mode of inheritance and
to identify distinct groups of patients for further molecular investigations.
Patients and Methods: Clinical examinations were carried out on 6
Caucasian patients and their affected first-degree relatives from 3
families with a family history of missing permanent teeth. Combined
examination of clinical phenotypes and orthopantomograms improved
the precision of diagnosis. Family study was used to determine whether
there is a hereditary basis for oligodontia or hypodontia.
Results: We describe tooth agenesis in three main groups: motherdaughter,
sister-sister and brother-sister. None of the patients and
their first-degree relatives shared similar patterns of missing teeth. No
correlation exists between the patterns of missing permanent teeth in
related individuals. Predominant dental phenotype involved anterior
teeth agenesis and symmetrical (left - right) hypodontia. Anomalies of
tooth-size and tooth-shape were also observed in association with hypodontia
but not with oligodontia. Gender difference did not influence
the severity of phenotype.
Conclusions: Multiplex family research allows for the study of inheritable
oligodontia/hypodontia, pattern of inheritance and genetic cause.
P02.088
Otopalatodigital syndrome type 2, perinatal approach and
identification of a new mutation in the Filamin A gene
M. Aguinaga1 , C. Yam1 , A. Hidalgo2 , D. G. Mayén1 ;
1 2 Instituto Nacional de Perinatología, Mexico City, Mexico, Hospital General de
México, Mexico City, Mexico.
Introduction: Otopalatodigital syndrome type 2 (OPD2) is part of the
so-called spectrum otopalatodigital disorders, it presents an X linked
mode of inheritance and males generally have a more severe phenotype
than women. Mutations responsible for the phenotype are found
in the FLNA gene located in Xq28, the Filamin A protein is widely expressed
and has an essential role in migration and cell morphology.
Case Report: Newborn mexican male patient, first pregnancy of
healthy and non-consanguineous parents. Prenatal ultrasound as-