2009 Vienna - European Society of Human Genetics

Cytogenetics
P03.062
Nine patients with a microdeletion 15q11.2 between breakpoints
1 and 2 of the Prader-Willi critical region: is it clinically relevant?
B. Sikkema-Raddatz 1 , M. Doornbos 2,3 , C. Ruijvenkamp 4 , T. Dijkhuizen 1 , E.
K. Bijlsma 4 , A. Gijsbers 4 , Y. Hilhorst-Hofstee 4 , R. Hordijk 1 , R. Verbruggen 2 , M.
Kerstjens-Frederikse 1 , T. v. Essen 1 , K. Kok 1 , A. v. Silfhout 1 , M. Breuning 4 , C. M.
A. van Ravenswaaij-Arts 1 ;
1 Department of Genetics; University Medical Centre, Groningen, The Netherlands,
2 Beatrix Children’s Hospital, University Medical Centre, Groningen, The
Netherlands, 3 Department of Paediatrics, Albert Schweitzer Hospital, Dordrecht,
The Netherlands, 4 Department of Clinical Genetics, Leiden University Medical
Centre, Leiden, The Netherlands.
Behavioural differences have been described in patients with type I deletions
(between breakpoints 1 and 3, (BP1-BP2)) or type II deletions
(between breakpoints 2 and 3) of the 15q11.2 Prader-Willi/Angelman
region. The larger type I deletions appear to coincide with more severe
behavioural problems (autism, ADHD, obsessive-compulsive disorder).
The non-imprinted chromosomal segment between breakpoints
1 and 2 involves four highly conserved genes, TUBGCP5, NIPA1,
NIPA2, and CYFIP1; the latter three are widely expressed in the central
nervous system, while TUBGCP5 is expressed in the subthalamic
nuclei. These genes might explain the more severe behavioural problems
seen in type I deletions.
We describe nine cases with a microdeletion at 15q11.2 between BP1-
BP2, thus having an haploinsufficiency for TUBGCP5, NIPA1, NIPA2,
and CYFIP1 without Prader-Willi/Angelman syndrome. The clinical
significance of a pure BP1-BP2 microdeletion has been debated, however,
our patients shared several clinical features, including delayed
motor and speech development, dysmorphisms and behavioural problems
(ADHD, autism, obsessive-compulsive behaviour). Although the
deletion often appeared to be inherited from a normal or mildly affected
parent, it was de novo in two cases and we did not find it in 350 healthy
unrelated controls.
Our results suggest a pathogenic nature for the BP1-BP2 microdeletion
and, although there obviously is an incomplete penetrance, they
support the existence of a novel microdeletion syndrome in 15q11.2.
P03.063
A 17q21.31 deletion associated with progressive muscle
hypertrophy and skeletal anomalies
V. M. Siu 1 , Y. S. Fan 2 ;
1 Department of Pediatrics, Schulich School of Medicine, University of Western
Ontario, London, ON, Canada, 2 Department of Pathology, University of Miami
Miller School of Medicine, Miami, FL, United States.
The 17q21.31 microdeletion is a recently described syndrome with
characteristic features of developmental delay, hypotonia, long face,
tubular or pear-shaped nose with bulbous nasal tip, and friendly behaviour.
We report an 18 year old young man with cognitive delay
who presented with hypotonia, bilateral radial head dislocation, laryngotracheomalacia,
bilateral inguinal hernias, broad thumbs, large
hands with fleshy fingers, seizure disorder, congenital partial fusion
of lower thoracic and lumbar vertebrae, and deep hoarse voice. His
facial features were strikingly similar to those previously reported in the
17q21.31 microdeletion syndrome and he had a very cheerful outgoing
personality. In early childhood, he had marked ligamentous laxity
and hypotonia, but his thigh muscles were prominent. After age 12,
he began to develop prominent musculature in his upper extremities,
without exercising. At age 18, he is quite strong and his muscle bulk
surpasses that of his normal brother who is very physically fit. Microarray-based
comparative genomic hybridization using a 44k oligo array
revealed a deletion of approximately 627 kb in the 17q21.31 region
(chr17: 41073486-41700815). The critical region for the 17q21.31
microdeletion syndrome consists of a 424 kb genomic segment
(chr17: 41046729-41470954, hg17) encompassing at least 6 genes
(C17orf69, CRHR1, IMP5, MAPT, STH, and KIAA1267). The proximal
deletion breakpoint in our patient is distal to that seen in previously reported
cases, possibly refining the critical region involved in the facial
dysmorphic features and behaviour. Haploinsufficiency for a gene in a
segment beyond the critical region may account for the muscle hypertrophy
and/or skeletal anomalies.
P03.064
clinical and molecular characterization of the 17q21.31
microdeletion syndrome in 11 French patients with mental
retardation
C. Dubourg 1,2 , J. Andrieux 3 , D. Sanlaville 4,5 , M. Doco-Fenzy 6,7 , C. Le Caignec 8 ,
C. Missirian 9 , S. Jaillard 10,2 , C. Schluth-Bolard 4,5 , E. Landais 6,7 , O. Boute 11 ,
N. Philip 9 , A. Toutain 12 , P. Edery 4,5 , A. Moncla 9 , D. Martin-Coignard 13 , C. Vincent-Delorme
14 , I. Mortemousque 12 , S. Drunat 15 , M. Berri 16 , R. Touraine 17 , S.
Odent 18,2 , V. David 1,2 , Réseau Français CGH-array;
1 Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes, France,
2 CNRS UMR 6061, Université de Rennes 1, IFR140, Rennes, France, 3 Laboratoire
de Génétique Médicale, Hôpital Jeanne de Flandre, Lille, France, 4 Laboratoire
de Cytogénétique, CBPE, Hospices Civils de Lyon, Bron, France, 5 Université
Claude Bernard Lyon I, Faculté de Médecine, Lyon Nord, France, 6 Service
de Génétique, HMB, CHRU, Reims, France, 7 EA 3801, UFR de Médecine,
Reims, France, 8 Service de Génétique Médicale, CHU, Nantes, France, 9 Département
de Génétique Médicale, Hôpital d’Enfants de la Timone, Marseille,
France, 10 Laboratoire de Cytogénétique, CHU Pontchaillou, Rennes, France,
11 Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France,
12 Service de Génétique, CHRU Hôpital Bretonneau, Tours, France, 13 Service de
Pédiatrie Génétique, CH, Le Mans, France, 14 Service de Pédiatrie Génétique,
CH, Arras, France, 15 Service de Génétique, CHU Hôpital Robert Debré, Paris,
France, 16 Service de Génétique, CHU Hôpital Brabois, Nancy, France, 17 Service
de Génétique Moléculaire, CHU Hôpital Nord, Saint-Etienne, France, 18 Service
de Génétique Médicale, CHU Hôpital Sud, Rennes, France.
Array comparative genomic hybridization has recently led to the characterization
of novel microdeletion and microduplication syndromes
like the 17q21.31 microdeletion syndrome.
Here we report the clinical and molecular characterization of 11 French
patients with mental retardation and with the 17q21.31 microdeletion
syndrome. We also present here the genotyping for H1/H2 and parentof-origin
analysis.
Several clinical features such as moderate mental retardation, childhood
hypotonia, low birth weight and facial dysmorphisms (long face,
tubular or pear-shaped nose and bulbous nasal tip) are common.
Other inconstant clinically features include epilepsy, heart defects and
kidney/urologic anomalies.
The described 17q21.31 critical region covers 424 kb and encompasses
five reference genes (CRHR1, IMP5, MAPT, STH and KIAA1267).
We report here a smaller ~ 200 kb deletion which encompasses only
MAPT, STH and KIAA1267. This narrowing of the critical region point
out the MAPT gene as candidate gene, especially since MAPT has
been associated with several neurodegenerative disorders.
All these deletions arise de novo. A 900 kb inversion polymorphism
exists in the 17q21.31 region and chromosomes with the inverted segment
in different orientations represent two distinct haplotypes, H1 and
H2. These different orientations are likely to facilitate the generation
of the microdeletion through an established mechanism of NAHR and
the offspring of carriers of the H2 lineage are predispose to deletion.
In each trio tested, the parent-of-origin of the deleted chromosome 17
carries at least one H2 chromosome and, for informative cases, 2/3 out
of deletions were of maternal origin and 1/3 of paternal origin.
P03.065
chromosome 1q21.1 deletion and duplication in the patient with
psychiatric problems
H. Kaymakcalan, M. Seashore, P. Li;
Yale University Department of Clinical Genetics, New Haven, CT, United
States.
Chromosome 1q21.1 deletions and duplications have recently been
reported to show associations with developmental delay, schizophrenia
and related psychoses, congenital heart defects, cataracts, micro
and macrocephaly.
We report a rare case of chromosome 1q21.1 deletion and duplication
in the same patient whose brother later presented with similar psychiatric
symptoms and similar chromosomal rearrangement.
An 8 year old female with PDD NOS, ADHD, expressive language
problems, developmental delay, mental retardation (IQ 60) and failure
to thrive presented with severe aggressive behaviour that necessitated
hospitalization. Her physical examination was remarkable for microcephaly
(