2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.298
Hyperphosphatasia with seizures, neurologic deficit and
characteristic facial features: Five new cases of mabry
syndrome
M. D. Thompson 1 , M. M. Nezarati 2 , G. Gillessen-Kaesbach 3 , P. Meinecke 4 , R.
Mendoza-Londono 5 , A. Munnich 6 , D. E. C. Cole 7 ;
1 Dept of Lab Medicine & Pathobiology, Univ. of Toronto, Toronto, ON, Canada,
2 Dept of Genetics, North York General Hospital, Toronto, ON, Canada, 3 Institut
für Humangenetik, Universität zu Lübeck, Germany, Lübeck, Germany,
4 Abteilung Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg,
Germany, 5 Dept of Pediatrics, Univ. of Toronto, Toronto, ON, Canada, 6 Hôpital
Necker-Enfants Malades, Paris, France, 7 Dept of Lab Medicine and Pathobiology
& Dept of Pediatrics, Univ. of Toronto, Toronto, ON, Canada.
In 1970, Mabry et al . described multiple cases of persistent hyperphosphatasia
associated with developmental delay and seizures in a
single consanguineous family (OMIM#239300) . The nosology of this
condition, however, is uncertain. We report five new cases that help
delineate this disorder and provide further evidence favouring autosomal
recessive inheritance, with sib recurrence in one instance (French
non-consanguinous parents), and consanguinity (Lebanese parents)
in another. Common to all five children is the Mabry triad of tonic-clonic
seizures (usually beginning around one year of age), moderate to severe
developmental delay, and persistently elevated alkaline phosphatase
activity, without any indication of liver or metabolic bone disease .
The degree of hyperphosphatasia varies considerably amongst cases
(~1 .3 to 20 times the upper age-adjusted reference limit) . In addition,
all five display a common facial dysmorphism, characterized by hypertelorism,
broad nasal bridge, and tented mouth . The three singleton
cases also have brachytelephalangy, but there is no evidence of skeletal
anomalies in the two siblings. In the family first described by Mabry
et al ., at least one affected was noted to have intracellular inclusions
on biopsy of rectal mucosa but not liver . In three of our cases, inclusions
have been observed in cultured cells, but the cells are not uniformly
perturbed and characterization is still in progress . We are aware
of additional cases in the literature which suggest a wider phenotypic
spectrum, but they are consistent with an autosomal recessive condition
characterized by hyperphosphatasia, seizures, and neurologic
deficit - a disorder we call Mabry syndrome.
P01.299
The yield of cascade screening and risk stratification for sudden
cardiac death in hypertrophic cardiomyopathy mYBPc3 gene
mutation carriers
I. Christiaans 1 , E. Birnie 2 , I. M. van Langen 1 , G. J. Bonsel 2 , A. A. M. Wilde 3 ;
1 Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The
Netherlands, 2 Institute of Health Policy and Management, Erasmus Medical
Centre, Rotterdam, The Netherlands, 3 Department of Cardiology, Academic
Medical Centre, Amsterdam, The Netherlands.
Background: Hypertrophic cardiomyopathy (HCM) is a common autosomal
dominant heart disease associated with heart failure and sudden
cardiac death (SCD) . Disease penetrance and the risk of SCD in
mutation carriers are unknown . We investigated the prevalence of a
clinical diagnosis of HCM and the presence of risk factors for SCD at
the first cardiological evaluation after presymptomatic genetic testing
in asymptomatic carriers of a MYBPC3 gene mutation .
Methods: 235 asymptomatic mutation carriers were cardiologically
evaluated on the presence of HCM and risk factors for SCD . A comparison
was made for different types of MYBPC3 gene mutations .
Results: A clinical diagnosis of HCM could be made in 22 .6% of carriers
. Disease penetrance at 65 years was incomplete for all types of
MYBPC3 gene mutations . Women were affected less often (p=0 .003)
and disease penetrance was lower (p=0 .024) . 22 asymptomatic carriers
had ≥ two risk factors for SCD. In nine a clinical diagnosis of HCM
could be made and they were therefore at high risk for SCD .
Conclusion: A diagnosis of HCM can be made in almost one quarter
of mutation carriers at first evaluation. Disease penetrance of HCM in
MYBPC3 gene mutation carriers is incomplete at 65 years and differs
between men and women . Risk factors were frequently present and
4% of carriers appeared to be at high risk for SCD . Our data justify
presymptomatic genetic testing in HCM families with a pathogenic mutation
and frequent cardiological evaluation on the presence of HCM
and risk factors for SCD, even until advanced age .
P01.300
Prevalence and phenotypic characteristics associated
with myBPc3 mutations in patients with hypertrophic
cardiomyopathy
M. Hermida-Prieto, M. I. Rodríguez-García, M. Ortiz, R. Barriales, X. Fernandez,
L. Cazón, I. Alvariño, A. Castro-Beiras, L. Monserrat;
Instituto de Ciencias de la Salud, La Coruña, Spain.
Background: Mutations in the beta-myosin heavy chain (MYH7) and
myosin-binding protein C (MyBPC3) genes are the most frequent
causes of hypertrophic cardiomyopathy (HCM) . MyBPC3 mutations
have been associated with later diagnosis and less hypertrophy than
MYH7 mutations . Our objectives were to compare the prevalence of
mutations and the phenotypic characteristics associated with both
genes in our patients with HCM .
Methods: SSCP analysis and sequencing of fragments with abnormal
MyBPC3 gene mobility were carried out in 130 consecutive index patients
with HCM previously studied for the MHY7 gene (10% mutated) .
The phenotypes of patients with and without mutations in both genes
were compared .
Results: We identified 16 MyBPC3 different mutations (8 of them novel)
in 20 patients (15 .4%) . Age at diagnosis was similar in MyBPC3 vs .
MYH7 patients (46 .2 vs . 46 .0, p ns) . More than 50% (11) of MyBPC3
mutated patients were diagnosed before 50 years of age, 35% (7) <
40 and 15% (3) < 30 . MyBPC3 patients had lower maximal thickness
(25 .15 vs . 30 .45 mm, p=0 .045) than those with mutations in MYH7, but
higher than non-mutated patients (22 .17 mm, p=0 .034) . Thirty percent
of MyBPC3 patients had a maximal wall thickness ≥ 28 mm (2 of them
with a thickness >40 mm were younger than 45 years old) .
Conclusions: MyBPC3 mutations were present in 15 .4% of our families
. Patients with MyBPC3 gene mutations were not older at diagnosis
than patients with MYH7 mutations . MyBPC3 mutations may appear in
young patients with severe hypertrophy .
P01.301
Espectrum of mutations in myBPc3 gene in 130 families with
hypertrofic cardiomyopathy
M. I. Rodríguez-García, L. Monserrat, L. Cazón, M. Ortiz, I. Alvariño, R. Barriales,
X. Fernández, A. Castro-Beiras, M. Hermida-Prieto;
Instituto Universitario de Ciencias de la Salud, A Coruña, Spain.
Hypertrophic cardiomyopathy (HCM), an autosomal-dominant disorder
and the leading cause of sudden cardiac death in the young, is caused
by mutations in genes encoding sarcomeric proteins . One of the most
common genetic causes for HCM involves mutations is MYBPC3, the
gene encoding cardiac myosin binding protein C .
To determine the spectrum of mutations in MyBPC3 gene, 130 index
cases were tested .
A total of 16 different mutations, including 8 novel ones, were identified
in 20 families (15.4%): 9 missense (D75N,A216T,V471E,R49
5W,R502Q[in 2 families], E542Q[in 3 families],T957S,R1022P[in 2
families],E1179K, 4 delections (Q327fs,K504del, K600fs,P955fs) and
3 intronic regions (IVS6+5G>A,IVS11-9G>A,IVS29+5G>A) .
Ten of the mutations were identified on 7 of the 34 exons studied.
Exons 16 and 17 could be “hot spots” due to the fact that 35% of the
families presented a mutation in these exons . The average of age in
the index cases with mutation was 50 years . Four carriers relatives
weren’t diagnosed HCM but they were below mean age of diagnose,
so it is possible that they haven’t yet developed the phenotype . Besides,
there were 3 relatives without conclusive diagnostic of HCM that
didn’t present mutation; this could suggest mutations in other genes .
In conclusion, MyBPC3 is one of the genes most commonly affected
by HCM-causing mutations which leads to a relatively mild phenotype
with an adult age of onset . Furthermore, the existence of individuals
with HCM but without mutation in MyBPC3, suggests the presence of
additional disease-causing mutations in other genes .
P01.302
Neuroblastoma (NB) with hypothalamic dysfunction (HD): report
of a series of 14 cases
J. Amiel, L. de Pontual, A. Nougayrede, A. Munnich, S. Lyonnet;
INSERM U-781, Department of Genetics, Necker Hospital, Paris, France, Paris,
France.
Neuroblastoma (NB) is a frequent paediatric tumour for which recurrent
somatic rearrangements are known . Congenital central hypoven-
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