2008 Barcelona - European Society of Human Genetics

Clinical genetics
skull defect, until bony tissue between the intracranial structures and
the overlying lesion could be identified. At 22 gestational weeks, the
mentioned fluid collection had disappeared, leaving a residual scalp
thickening and an enlarged nuchal fold . Fetal karyotype by amniocentesis
was normal (46,XY) . At birth, the infant showed a Noonan syndrome
phenotype and a CVG .
Discussion: CVG is possibly due to an initial scalp lymphedema and
its further resolution, and should be distinguished from a cephalocele .
This is the third description of a patient with Noonan syndrome and
CVG, and the second describing a fluid collection at the cephalic pole
that progressed to CVG . The observed images and their evolution are
of clinical importance, because they can strengthen the suspicion of
Noonan syndrome prenatally .
P01.183
Gain-of-function RAF mutations cause Noonan and LEOPARD
syndromes with hypertrophic cardiomyopathy
B. Pandit 1 , A. Sarkozy 2 , L. Pennacchio 3 , C. Carta 4 , K. Oishi 1 , S. Martinelli 4 , W.
Schackwitz 3 , A. Ustaszewska 3 , S. R. Ommen 5 , F. Lepri 2 , C. Faul 1 , P. Mundel 1 ,
J. P. López Siguero 6 , R. Tenconi 7 , A. Selicorni 8 , C. Rossi 9 , L. Mazzanti 9 , I.
Torrente 2 , B. Marino 10 , M. C. Digilio 11 , G. Zampino 12 , M. J. Ackerman 5 , B. Dallapiccola
2 , M. Tartaglia 4 , B. D. Gelb 1 ;
1 Mount Sinai School of Medicine, New York, NY, United States, 2 CSS-Mendel
Institute, Rome, Italy, 3 Lawrence Berkeley National Laboratory, Berkeley, CA,
United States, 4 Istituto Superiore di Sanità, Rome, Italy, 5 Mayo Clinic College
of Medicine, Rochester, MN, United States, 6 Hospital Materno-Infantil, Málaga,
Spain, 7 Università di Padova, Padua, Italy, 8 Università di Milano, Milano, Italy,
9 Policlinico S. Orsola-Malpighi, Università di Bologna, Bologna, Italy, 10 Policlinico
“Umberto I”, Università di Roma “La Sapienza”, Rome, Italy, 11 Ospedale
“Bambino Gesù”, Rome, Italy, 12 Università Cattolica del Sacro Cuore, Rome,
Italy.
Noonan and LEOPARD syndromes (NS and LS) are developmental
disorders with overlapping features including cardiac abnormalities,
short stature and facial dysmorphisms . Increased RAS signaling due
to PTPN11, KRAS and SOS1 mutations cause approximately 60% of
NS cases, while PTPN11 mutations cause approximately 90% of LS
cases . Here, we report that 18 of 231 NS and two of six LS patients
without mutations in known genes have missense mutations in RAF1,
which encodes a serine/threonine protein kinase that activates MEK1
and MEK2. Most mutations altered a motif flanking Ser259, a residue
critical for RAF1’s autoinhibition through 14-3-3 binding . RAF1 mutations
in two hotspots were strongly associated with hypertrophic cardiomyopathy
(HCM; 95% vs . 18% of all NS) . Ectopically expressed
RAF1 mutants from HCM clusters had increased kinase activity and
enhanced ERK activation, while non-HCM-associated-cluster mutants
were kinase impaired. Our findings further implicate increased RAS
signaling in pathological cardiomyocyte hypertrophy .
P01.184
sOs1 mutation in a cFc patient
M. Somer1 , M. L. Väisänen2 , M. Lähde3 , J. Ignatius2 ;
1Dept Medical Genetics, The Family Federation of Finland, Helsinki, Finland,
2 3 Oulu University Hospital, Oulu, Finland, North Carelian Central Hospital, Joensuu,
Finland.
After the CFC syndrome was originally published in 1986 it was continuously
debated whether it can be separated from the Noonan syndrome
. Molecular genetic studies have shown that at least one gene
in the RAS pathway, KRAS can cause both syndromes . When SOS1
was described to be the second most common gene in Noonan it was
emphasized that it usually does not cause the CFC syndrome . We
describe a 4-y-o boy with SOS1 exon 6 missense mutation c .797C>A
(p .T266K), earlier reported by Roberts et al in 2007 in a Noonan patient
. Parental studies were normal . He was born at after 37 weeks of
pregnancy complicated by fetal hydronephrosis and polyhydramnios
with birth weight 4000g, length 51 cm and OFC 36,5 cm . There was
oedema, opistothonus, poor feeding, cryptorhidism, and umbilical hernia
. He has pulmonary and mild aortic stenosis, ASD secundum, and
hypertrophy of the ventricular septum . His growth is on the -1 .2 SD
curve and OFC +1 .5 SD . He started to walk at 18 months but is not
yet able to run. He spoke the first words at 3,5 years and mainly uses
sign language . He has melatonin treatment for poor sleeping patterns .
Dysmorphic features are compatible with the CFC syndrome with bitemporal
constrictions, sparse hair, absent eyebrows, dystrophic nails
and hyperkeratotic eczema on face and legs . SOS1 mutation found in
this patient with CFC phenotype further emphasizes the need of phenotype-genotype
correlation studies in SOS1 mutation patients .
P01.185
improved mutation Detection in the Polygenic Disorders Noonan
syndrome and LEOPARD syndrome
S. Ramos 1 , J. Short 1 , N. Elanko 1 , K. Kalidas 2 , S. Cottrell 1 , R. Poh 1 , R. Taylor 1 ;
1 South West Thames Molecular Genetics Laboratory, St George’s Hospital,
London, United Kingdom, 2 Clinical Developmental Sciences, St George’s University
of London, London, United Kingdom.
Noonan syndrome (NS) is a common autosomal dominant multiple
congenital anomaly syndrome exhibiting short stature, heart defects
and facial dysmorphism . LEOPARD syndrome (LS) is a rare autosomal
dominant multiple congenital abnormality syndrome . The acronym
LEOPARD defines the common features: multiple Lentigines, ECG
conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis,
Abnormal genitalia, Retardation of growth and sensorineural Deafness
. Defects in the RAS-MAPK pathway have been implicated in both
syndromes .
Since 2001 missense mutations in the PTPN11 gene have been recognised
as causative in approximately half of NS cases and the majority
of LS cases . We established a service in 2002 to analyse exons 3 and
8 of this gene which contain ~80% of known NS mutations . Since 2005
we have screened all exons in which mutations had been identified
and thus allowed molecular confirmation of LS.
Mutations in the SOS1, RAF1 and KRAS genes, which also encode
proteins in the RAS-MAPK pathway, have been identified in 10-20% of
PTPN11 negative NS cases . RAF1 mutations have also been identified
in a proportion of PTPN11 negative LS cases . We have set up a
diagnostic service to analyse the known mutation-containing exons of
SOS1 and RAF1 and all exons of KRAS . Testing involves a dHPLC
pre-screen followed by bidirectional sequencing of any variants . We
have identified 12 pathogenic mutations in SOS1 and RAF1 in our
initial cohort of 110 PTPN11 negative cases referred for NS/LS . This
analysis is now integrated with the PTPN11 screen to facilitate a comprehensive
molecular investigation of NS and LS referrals .
P01.186
molecular analysis of the PtPN11 (protein-tyrosine phosphatase,
nonreceptor-type 11) gene in Estonian patients with Noonan
syndrome
I. Kalev 1 , K. Muru 2 , M. Zimmermann 3 , T. Reimand 4 , R. Teek 4 , S. Virro 5 , M.
Sõnajalg 5 , K. Õunap 6 ;
1 Department of Human Biology and Genetics, Institute of General and Molecular
Pathology, University of Tartu, Tartu, Estonia, 2 Department of Human
Biology and Genetics, Institute of General and Molecular Pathology, University
of Tartu; Department of Genetics, United Laboratories, Tartu University, Tartu,
Estonia, 3 Department of Human Biology and Genetics, Institute of General and
Molecular Pathology, University of Tartu; Department of Cell Biology, Institute of
Molecular and Cell Biology, University of Tartu, Tartu, Estonia, 4 Department of
Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia, 5 Children’s
Clinic, Tartu University Hospital, Tartu, Estonia, 6 Department of Genetics,
United Laboratories,Tartu University Hospital; Department of Pediatrics, University
of Tartu, Tartu, Estonia.
Noonan syndrome (NS; OMIM# 163950) is a relatively common
(1:1000-2500) autosomal dominant disorder characterized by proportional
short stature, facial dysmorphisms and cardiac anomalies . Missense
mutations of PTPN11 gene have been documented in about
50% of NS cases, while molecular lesions of other genes of the RAS
pathway (KRAS, SOS1, RAS1) play a minor role in the molecular
pathogenesis of the disease .
Study group consisted of 10 probands (age 1-36 y; 5 males/5 females),
4 of which were familial cases . All patients had the typical face and
inclusion diagnostic criteria of NS proposed by van der Burgt (1994) .
All of the patients had a normal karyotype . Sequence analysis was
performed for five coding PTPN11 exons 3, 4, 7, 8, 13 and their flanking
regions . Mutation analysis of the PTPN11 hot spot coding exons
revealed two different heterozygous missense mutations in two unrelated
families . A transition A1510G in exon13 for family NS-VI, which
predicts the Met504Val substitution, was described previously (Tartaglia,
2001), resided in the PTP domain of SHP-2 protein . A172G tran-