2009 Vienna - European Society of Human Genetics

Cytogenetics
All detected anomalies are available on the BACH database (https://
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P03.090
creating a First-Generation chromosome 18 Gene Dosage map
C. D. Sebold, E. C. Carter, P. L. Heard, D. E. Hale, J. D. Cody;
Chromosome 18 Clinical Research Center, San Antonio, TX, United States.
Background. Microarray technology has revolutionized the field of
clinical genetics. For individuals with chromosome abnormalities, the
promise of microarray technology is that it can quickly identify which
genes are and are not present in two copies. In order for this information
to be useful to clinicians, there must be some tool to link genotypic
data with annotated phenotypic information. As an initial step towards
this goal, we have created a first generation gene dosage map for
chromosome 18. Methods. Data from OMIM, the Database of Genomic
Variants, and medical and scientific manuscripts were reviewed
for each of the genes shown on the UCSC Genome Browser using
the March 2006 assembly. 253 genes were classified as haplosufficient,
haploinsufficient, conditional haplosufficient, or haplolethal. This
information, along with our data on critical regions for 18q- phenotypic
features, was used to create a custom track on the UCSC genome
browser. Results and Discussion. Eighty-one genes were determined
to be haplosufficient; 4 were haploinsufficient, and 1 was conditional
haploinsufficient. The effects of the non-haploid state in the
remaining genes were unknown. Critical regions for aural atresia, renal
abnormalities, growth hormone deficiency, and dysmyelination were
also included on the custom track. This map allows clinicians to align
the molecular karyotype information from an individual patient with the
annotated genomic content so as to provide a clinical prognosis. Thus,
we have taken the first step towards creating a genomic map that may
be used in counseling and directing care of individuals with chromosome
18 abnormalities.
P03.091
copy number mutations on chromosome 17q24.2-q24.3 linked to
congenital generalized hypertrichosis terminalis with or without
gingival hyperplasia
M. Sun 1 , N. Li 2 , W. Dong 3 , Z. Chen 4 , J. Yu 5 , L. He 6 , X. Zhang 1,2 ;
1 Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,
China, 2 China Medical University, Shenyang, China, 3 The Liaoning Province
People’s Hospital, Shenyang, China, 4 UCLA School of Medicine, Los Angeles,
CA, United States, 5 Beijing Institute of Genomics, CAS, Beijing, China,
6 Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Congenital generalized hypertrichosis terminalis (CGHT) is characterized
by excessive universal growth of pigmented terminal hairs. In
the present study, we describe three Han Chinese families with CGHT
and a sporadic case with extreme CGHT and gingival hyperplasia. We
performed linkage analysis in a large four-generation family and identified
a CGHT locus at chromosome 17q24.2-q24.3. We then carried
out copy number analysis with the Affymatrix Genome-Wide Human
SNP Array 6.0 and found nonrecurrent microdeletions in three CGHT
families and a larger microduplication in the sporadic case with extreme
CGHT and gingival hyperplasia. We validated all the copy number
variations (CNVs) by real-time quantitative PCR, and showed that
the microdeletions segregated with the disease phenotype in the three
families and the microduplication in the sporadic case was de novo
in origin. These CNVs shared a common overlapping genomic region
encompassing the mitogen-activated protein kinase kinase 6 gene,
MAP2K6. CNV at the MAP2K6 locus is not reported in the public database
and was not detected in normal Han Chinese population. Taken
together, our results strongly suggested that the CNVs on 17q24.2q24.3
were pathogenic copy number mutations responsible for CGHT
with or without gingival hyperplasia. This report identifies CGHT as a
genomic disorder and might suggest an important functional role of the
MAP2K6 gene in hair growth control.
P03.092
De Novo interstitial deletion 7p15.1p21 Encompassing the
tWist1 Gene in a Boy with craniosynostosis, marked Lacuna
skull and Facial Dysmorphism but Without Limb and spine
Defects
C. LI;
Mcmaster University Medical Center, Hamilton, ON, Canada.
A baby boy, delivered at 41weeks +3/7 days gestation to a healthy
29 year-old G1P0 after an essentially unremarkable pregnancy, was
noted to have strikingly abnormal skull shape, abnormal fontanels and
cranial sutures as well as facial dysmorphism that included abnormal
anterior hairline, supraorbital creases below and above the eyebrows,
shallow orbits, a deep transverse crease over the nose bridge and
an upturned nose with under developed nares. The ears were simple
with prominent superior and inferior crus of antihelix and the stem of
antihelix. The mouth was held open with tented upper lip. The palate
was extremely narrow but without clefting. Microretrognathia was evident.
He also had an extremely anteriorly placed anus. The genitalia
were otherwise normal. The rest of the clinical examination, including
the extremities, was normal. Head CT and MRI revealed craniosynostosis
of the coronal, lamdoid and metopic sutures and partial fusion
of the sagittal suture, a fenestrated lacuna skull with ventriculomegaly
and a hypoplastic corpus callosum. Skeletal survey showed
no spine and limb anomalies. He had an abnormal male karyotype
46,XY,del(7)(p15.1p21) but parental karyotype was normal. The deleted
region encompasses TWIST1 gene among several known and
presumably many unknown genes. TWIST1 is known to be involved in
Saethre-Chotzen syndrome, a condition characterized by craniosynostosis,
facial asymmetry, abnormal ears and digital anomalies, and less
commonly with parietal foramina, radioulnar synostosis, cleft palate
and congenital heart malformation. This case exhibited many features
of SCS but without spine and limb anomalies, although several novel
features were also noted.
P03.093
New case of interstitial 1q44 microdeletion and confirmation of a
critical region for corpus callosum abnormalities.
C. Rooryck Thambo1,2 , D. Cailley2 , M. Delrue2 , D. Lacombe1,1 , B. Arveiler1,2 ;
1 2 Laboratoire de Génétique Humaine, Bordeaux, France, Service de Génétique
Médicale CHU Pellegrin, Bordeaux, France.
We identified by array-CGH (oligonucleotides 105K, Agilent Technologies)
an interstitial 1q44 deletion, spanning about 2.1 Mb, in a patient
with mental retardation, dysmorphic features and brain abnormalities.
This deletion arose de novo. The proposita was the only child
of healthy non-consanguineous parents. She was born at term: birthweight
was 3060 g (M), length 49 cm (M), and OFC 35 cm (M). Family
history is non-contributory. At 30 months, height was 82 cm (-2.5 SD),
weight was 11 kg (-1 SD) and OFC was 47 cm (-1 SD). Clinical features
included brachycephaly, facial dysmorphism with deep set eyes,
synophris, horizontal eyebrows, prognathism, clinodactyly of fifth fingers,
flat feet. She walked unaided at 24 months and had no speech.
She had clonic seizures. Brain MRI showed hypoplasia of the anterior
part of corpus callosum, and veinous angioma in the right frontal lobe.
Electroencephalogram showed central epileptic spikes predominating
on the left side. This patient shows common clinical features to the
individuals with 1q44 deletions. This deletion involves 10 genes and
comprises the critical region for corpus callosum abnormalities described
by van Bon BWM et al., J Med Genet 2008, 45:346-354.
P03.094
A case of partial trisomy/monosomy of chromosome 8p
associated with autism and epilepsy defined by genome arraycGH
A. Nucaro 1 , R. Rossino 2 , F. Boscarelli 3 , S. Zorco 3 , N. Santini 3 , C. Montaldo 3 , I.
Chillotti 4 , D. Pruna 4 , T. Pisano 4 , C. Cianchetti 4 ;
1 Istituto di Neurogenetica e Neurofarmacologia, Monserrato( Cagliari), Italy,
2 Dipartimento di Scienze pediatriche e Medicina Clinica- University, Cagliari,
Italy, 3 Dipartimento di Scienze Chirurgiche e Odontostomatologiche, University,
Cagliari, Italy, 4 Clinica di Neuropsichiatria Infantile, Azienda Ospedaliero- Universitaria,
Cagliari, Italy.
Autism is a neurodevelopmental disorder with early childhood onset
and a prevalence of as much as 5/10,000. Symptoms that may contribute
throughout life include qualitative impairments in reciprocal com-