European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
tis media, abcesses, and…..). This disease was reported by Kostman
in a large consanguineous family from Northern part of the Sweden
(1956).
In this report we will present an Iranian family, with two affected children.
Parents are second cousins. Both of the sibs showed neutropenia
from early infancy. They have had recurrent severe bacterial infections.
The older one was a boy, that showed Myelodysplastic(MDS) changes
after the age of 15 and died from AML when he was 16-year-old. The
younger one is a 14-year-old girl just with the similar symptoms.
The response of both of them was favorable to G-CSF.
Mutation analysis of the ELA2 gene by direct DNA sequencing of PCRamplified
genomic DNA did not identify any abnormalities.
In searching of mutations in other candidate genes a homozygous mutation
found in HAX1 gene in the proband, and each of the parents was
heterozygous carrier for the mutation.
The mutation was W44X, same as described by Klein & Welte in their
Nature Genetics paper.
P0063. A de novo novel missense mutation in Connexin 26 in a
sporadic dominant case of non-syndromic deafness.
L. C. Trotta1 , P. Primignani1 , P. Castorina1 , F. Lalatta1 , C. Curcio1 , U. Ambrosetti1
, A. Cesarani1 , D. Cuda2 , A. Murri2 , M. Travi1 , D. A. Coviello1 ;
1Fondazione IRCCS Opedale Maggiore Policlinico, Mangiagalli e Regina Elena,
Milan, Italy, 2A.O. “Guglielmo da Saliceto”, Piacenza, Italy.
Mutations in the Connexin 26 gene (GJB2) can cause non-syndromic
recessive or dominant hearing loss (HL) or both sensorineural hearing
impairment and keratoderma.
We report here a novel missense dominant mutation of GJB2 gene associated
with non-syndromic deafness, identified in a 3 year old Italian
girl who has congenital profound sensorineural HL without skin disease
or other clinical features.
Patient’s DNA sequencing revealed an heterozygous C→G change at
nucleotide 172 resulting in a proline to alanine substitution at codon
58 (P58A).
No further sequence variants were revealed in the remaining coding
sequence and in the 5’UTR exon1.
We also excluded the reported deletions of Cx30, that is tightly linked to
GJB2 at 13q12, the Δ(GJB6-D13S1830) and the Δ(GJB6-D13S1854)
that are the cause of deafness in patients carrying one recessive GJB2
mutation in trans.
Parents were shown not to carry the P58A mutation and no other family
members were reported to have a significant hearing impairment.
Segregation analysis of 10 polymorphic microsatellite markers (from
chromosomes 13, 18, 21 and X) confirmed the correct presence of
bi-parental contribution.
This mutation was not observed among 100 healthy controls and 720
unrelated affected individuals, excluding it as a common polymorphism.
Proline at codon 58 is conserved among all connexins, suggesting that
this residue is critical for the function of the protein. This mutation occurs
in the first extracellular domain of the protein (EC1), which seems
to be very important for connexon-connexon interaction and for the
control of voltage gating of the channel.
P0064. Frequency of consanguinity and positive familial history
of disability or birth defect in yazd province
A. S. H. A. Dehghani Tafti;
Yazd Welfar Org, Yazd, Islamic Republic of Iran.
Consanguinity (family intermarriage) is commonly practiced in many
Asian, African and Latin American communities. In some countries
such as Iran consanguinity as in mating of first cousins is encouraged
as part of social customs. This study was performed on 3957 couples
that were referred to genetic counseling center of Yazd welfare organization
(from 2001 to 2007). Of these, 690 couples had a child with
disability or birth defect. The frequency of non-consanguineous marriages
was 31.6 % (218 couples) and the frequency of consanguineous
marriages was 68.4 % (472 couples). 52.9% of consanguineous
couples were first cousins and 15.5% were other relationship .In fact
consanguinity was so high and considerable. Furthermore, 34.5 % (238
cases) had a positive familial history of the same disability (in parents,
siblings and relatives). The most common kind of disability was mental
retardation (45.8%) and the least frequent problem was skin disorder
(0.3%). Children with chromosomal abnormality constituted 6.4% of
the cases. We conclude that the offspring of family intermarriages
have a significantly increased incidence of hereditary diseases.
P0065. Deletion of 8p23.1 with Features of Cornelia de Lange
Syndrome and Congenital Diaphragmatic Hernia and a Review
of Deletions of 8q23.1 to 8pter. ? A Further Locus for Cornelia de
Lange Syndrome
G. S. Baynam, I. Walpole, J. Goldblatt;
Genetic Services of Western Australia, Perth, Australia.
Cornelia de Lange syndrome is characterised by facial dysmorphism;
hirsutism and internal organ anomalies, including diaphragmatic hernia,
and limb defects. Causative mutations in two genes have been
identified: (1) NIPBL on chromosome 5q13 is dominantly inherited
and accounts for approximately 50% of cases and (2) SMC1L1 (also
known as SMC1) on the X chromosome, shows X-linked inheritance
and accounts for an unknown proportion of cases. However, the aetiology
of a significant number of cases remains unknown. A variety of
chromosomal anomalies have been described in a minority of cases.
We report on a child with an 8p23.1 deletion with features of CdLS
and congenital diaphragmatic hernia. We review cases with cytogenetic
anomalies involving 8p23.1 and discuss potential relationships
between 8p23.1 deletions and CdLS or impaired cohesin complex
function.
P0066. NIPBL mutational analysis in 56 individuals with Cornelia
de Lange Syndrome
M. Zarhrate, G. Borck, L. Colleaux, A. Munnich, V. Cormier Daire, J. Bonnefont;
INSERM U781 and Department of Genetics, Hospital Necker Enfants Malades,
Paris, France, Paris, France.
Cornelia de Lange syndrome (CdLS) is characterised by facial dysmorphism,
microcephaly, growth and mental retardation, hirsutism,
gastroesophageal reflux and congenital anomalies including limb defects.
Mutations in the gene NIPBL, the human homolog of Drosophila
Nipped-B, have recently been found in approximately 50% of CdLS
cases. The function of NIPBL in mammals is unknown. We present
here the molecular analysis of a series of 56 children with typical features
of CdLS including two-father-to child transmissions . Multiplex
ligation-dependent probe amplification (MLPA) screening failed to detect
either partial or whole-gene NIPBL deletions in 15 patients tested.
Direct sequencing of the 47 NIPBL exons and corresponding exon-intron
boundaries enabled to identify 21 heterozygous NIPBL mutations
including eight missense (38%), one nonsense (4%), four frameshift
(19%), one 5’UTR (4%) and seven splice site mutations (33%). These
mutations were not found in 100 control chromosomes.
Our study confirms that NIPBL mutations account for about 40% of
CdLS cases. We detected three SMC1L1 mutations in the same patient
series. Absence of NIPBL mutation in the remaining cases further
supports genetic heterogeneity of the disorder. Finally, the observation
of two familial mutations in our series suggests that parent-to-child
transmission may have been underestimated so far.
P0067. Incidence and clinical features of X-linked Cornelia de
Lange syndrome due to SMC1L1 mutations
G. Borck, M. Zarhrate, J. P. Bonnefont, A. Munnich, V. Cormier-Daire, L. Colleaux;
Department of Medical Genetics and INSERM U781, Hôpital Necker- Enfants
Malades, Paris, Paris, France.
Cornelia de Lange syndrome (CdLS) is a multisystem developmental
disorder characterized by facial dysmorphism, growth and mental
retardation, microcephaly, and various malformations. Heterozygous
mutations in the NIPBL gene have been detected in approximately
45% of affected individuals. Recently, a second CdLS gene, mapping
to the X chromosome, has been identified: SMC1L1 (structural maintenance
of chromosomes 1-like 1; or SMC1A). In order to estimate
the incidence and refine the clinical presentation of X-linked CdLS, we
have screened a series of 11 CdLS boys carrying no NIPBL anomaly.
We have identified two novel de novo SMC1L1 missense mutations
(c.587G>A [p.Arg196His] and c.3254A>G [p.Tyr1085Cys]). Our results
confirm that SMC1L1 mutations cause CdLS and support the view that
SMC1L1 accounts for a significant fraction of boys with unexplained
CdLS. Furthermore, we suggest that SMC1L1 mutations have milder
effects than NIPBL mutations with respect to pre- and postnatal
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