2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.334
Identification of a novel NOTCH1 mutation in patient with
bicuspid aortic valve disease and thoracic aortic aneurysm
M. Diegoli1 , M. Grasso2 , N. Marziliano2 , A. Serio2 , A. Pilotto2 , M. Pasotti2 , E.
Serafini2 , E. Porcu2 , P. Cassini2 , A. Brega3 , E. Arbustini2 ;
1 2 University of Pavia, PAVIA, Italy, IRCCS Policlinico San Matteo, PAVIA, Italy,
3University of Milano, MILANO, Italy.
The bicuspid aortic valve (BAV) (MIM#109730) is the most common
congenital cardiac malformation, occurring in 1-2% of the population .
This condition is associated with a significantly increased risk of developing
thoracic aortic aneurysms and acute aortic dissection . The
valve calcification often observed in BAV is a result of inappropriate
activation of osteoblast-specific gene expression. Recently, an association
between mutations in NOTCH1 gene and aortic valve disease
has been described . NOTCH1 encodes for a transmembrane protein
that activates a signaling pathway with an active role in cardiac embryogenesis,
including aortic and pulmonary valve development .
A 52-year old male was referred to our attention for suspected Marfan
Syndrome. The patient did not fulfil Ghent criteria for Marfan Syndrome
. He presented dilatation of the aortic root, the ascending aorta,
and bicuspid and calcified aortic valve.
The family history was positive for autosomal dominant aneurysm of
the ascending aorta not associated with other syndromic features .
The candidate gene NOTCH1 was screened by DHPLC and sequencing
of heteroduplex amplicons .
A novel c .C4104T transition predicting the missense p .Ala1343Val mutation
was identified in exon 25.
This result brings the attention of clinical geneticists to evaluate the
NOTCH1 gene in patients with early onset of calcific and bicuspid aortic
valve as plausible causative gene in the light of preventive surgery
for carryers of gene defects and mild to severe aortic root dilation .
Furthermore, this gene should be carefully evaluated in patients with
toracic aneurism dissection without syndromic features previously
genotyped for TGFBR1 and TGFBR2 genes with negative results .
P01.335
R229Q and A284 mutations of NHPs2 gene likely cause of
steroid resistant nephrotic syndrome
A. Zuniga, S. Sanchez, S. Ferrando, A. Guerrero;
Hospital de la Ribera, Alzira (Valencia), Spain.
The idiopathic nephrotic syndrome is a clinical pathologic entity occurring
mainly in children and is characterized by massive proteinuria,
hypoalbuminemia, hyperlipidemia, edema, and minimal glomerular
changes . In some instances, renal biopsy may show focal segmental
glomerulosclerosis (FSGS) or diffuse mesangial proliferation . In contrast
to 2 types of hereditary nephrotic syndrome previously identified,
congenital nephrosis of the Finnish type (OMIM 256300) and diffuse
mesangial sclerosis (OMIM 256370), idiopathic nephrotic syndrome
was generally regarded as a sporadic disease although a few familial
cases had been reported . Most patients with idiopathic nephrotic
syndrome respond to steroid therapy and show a favorable outcome .
However, 20% are steroid-resistant, with progression to end-stage renal
failure in many cases . The nephrotic syndrome may recur after
renal transplantation in such cases . NPHS2 mutations will be found
in sporadic cases of steroid-resistant idiopathic nephrotic syndrome,
which represents an important cause of childhood end-stage renal disease
. The detection of NPHS2 mutations is of clinical utility as it would
prescribe against unnecessary immunosuppressive therapy .
A 12-year-old girl was referred to our laboratory with a diagnosis of steroid-resistant
nephrotic syndrome from pediatric nephrology department
. We have analyzed PCR amplicons of each of the eight exons of
NPHS2 by direct sequencing and we have found that she was carrier
of two mutations: R229Q and A284V . The R229Q mutation alone is insufficient
to cause FSGS but the presence of a second A284V NPHS2
mutation on the other allele suggests that compound heterozygosity
for these sequence changes is the likely cause of disease .
P01.336
mutational spectrum of BCOR gene in Oculo-Facio-cardio-
Dental (OFcD) syndrome
S. Whalen 1 , E. Hilton 2 , J. Johnston 3 , N. Okamoto 4 , Y. Hatsukawa 5 , J. Nishio 6 , S.
Mizuno 7 , C. Torii 8 , K. Kosaki 8 , S. Manouvrier 9 , O. Boute 9 , R. Perveen 2 , C. Law 10 ,
A. Moore 11 , J. Lemke 12 , F. Fellmann 13 , M. Gerard 14 , M. Goossens 1 , A. Verloes 14 ,
A. Schinzel 12 , D. Bartholdi 12 , W. Reardon 15 , L. Biesecker 3 , G. Black 2 , I. Giurgea 1 ;
1 Département de Génétique, Institut Mondor de Recherche Biomédicale, IN-
SERM U841, Créteil, France, 2 Academic Unit of Medical Genetics, St Mary’s
Hospital, Manchester, United Kingdom, 3 Genetic Disease Research Branch,
National Human Genome Research Institute, NIH, Bethesda, MD, United
States, 4 Department of Planning and Research, Osaka Medical Centre and
Research Institute, for Maternal and Child Health, Osaka, Japan, 5 Department
of Ophthalmology, Osaka Medical Centre and Research Institute, for Maternal
and Child Health, Osaka, Japan, 6 Department of Oral and Maxillofacial Surgery,
Osaka Medical Centre and Research Institute, for Maternal and Child Health,
Osaka, Japan, 7 Department of Pediatrics, Central Hospital, Aichi Human Service
Centre, Kasugai, Japan, 8 Department of Pediatrics, Keio University School
of Medicine, Tokyo, Japan, 9 Service de Génétique Clinique, Centre Hospitalier
Régional Universitaire de Lille, Lille, France, 10 Wessex Clinical Genetics Service,
Princess Anne Hospital, Southampton, United Kingdom, 11 Moorfields Eye
Hospital, London, United Kingdom, 12 Institut für Medizinische Genetik, Universität
Zürich, Zürich, Switzerland, 13 Service de Génétique Médicale, Centre
Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 14 Département de
Génétique Médicale, Hôpital Robert Debré, Paris, France, 15 National Centre
for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin,
Ireland.
Background: OFCD syndrome is characterized by ocular defects
(congenital cataract, microphthalmia), facial dysmorphia, congenital
cardiac defects, dental irregularities (radiculomegaly, oligodontia) and
skeletal deformities . It results from mutations in BCOR gene localized
on Xp11 .4 . All affected individuals are females and the few reported
mutations are either deletions or generate premature stop codons . A
single missense variant was identified within BCOR in a family with
Lenz microphthalmia syndrome . OFCD syndrome has been shown to
encompass defects of laterality, including the heart and other viscera .
Methods: We analyzed BCOR gene in 26 female patients diagnosed
with OFCD syndrome, 21 males with Lenz microphtalmia, 96 patients
with isolated microphtalmia and 96 patients with cardiac laterality defects
.
Results: Mutations were identified for the 26 patients with OFCD syndrome,
and one patient with “isolated” microphtalmia . The same previously
reported missense variant was identified in a boy with Lenz
microphthalmia syndrome. No mutation vas identified in the other patients
tested . We report somatic mosaicism of BCOR anomalies in two
families with OFCD syndrome . In both families, the mothers had 50%
mosaicism in leucocytes, and their daughters carried the mother’s mutation
homogeneously. In the first family the mother, her monozygotic
twin sister and her daughter were affected . In the second family, the
daughter was affected but not her mother .
Conclusion: We report 27 novel patients with OFCD syndrome and
mutations in BCOR gene . Cataract and radiculomegaly seem to be the
two constant clinical signs in OFCD syndrome . Mosaicism in two of our
families advocates cautiousness in genetic counselling .
P01.337
clinical heterogeneity in cases of oral clefts with multiple
congenital anomalies
E. Preiksaitienė 1 , A. Matulevičienė 1,2 , A. Utkus 1,2 , V. Kučinskas 1,2 ;
1 Department of Human and Medical Genetics, Faculty of Medicine, Vilnius
University, Vilnius, Lithuania, 2 Centre for Medical Genetics at Vilnius University
Hospital Santariškių Klinikos, Vilnius, Lithuania.
The causes of oral clefts (OCs) are multiple and complex, but the first
step in the search of genetic basis should be epidemiological and
clinical data . Although cleft palate (CP) is usually regarded as distinct
defect from cleft lip with or without cleft palate, there is still an open
question if the latter should be considered as variants of the same
defect or should be divided into groups of cleft lip only (CL) and cleft lip
with cleft palate (CLP) . In the retrospective study of multiple congenital
anomalies (MCA) of unknown origin in cases of oral clefts in Lithuania
the incidence of anomalies associated with OCs was calculated
among all three groups: CL, CP and CLP . There were 434 associated
anomalies in 143 cases of OCs with MCA . Most frequently affected
was the musculoskeletal system (31 .6%, 137 anomalies), followed by
cardiovascular (21 .7%, 94), but a more detailed analysis of CL and
CLP cases revealed some differences in the incidence and type of
associated anomalies . Cardiovascular anomalies were the most common
associated anomalies (30 .1%), followed by musculoskeletal
(23 .8%) and congenital anomalies of ear, face and neck (20 .6%) in