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Submicroscopic chromosomal imbalances in idiopathic Silver-Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome


Spengler, S; Schönherr, N; Binder, G; Wollmann, H; Fricke-Otto, S; Mühlenberg, R; Denecke, B; Baudis, M; Eggermann, T (2010). Submicroscopic chromosomal imbalances in idiopathic Silver-Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome. Journal of Medical Genetics, 47(5):356-360.

Abstract

Silver-Russell syndrome (SRS) is a heterogeneous disorder associated with intrauterine and postnatal growth restriction, body asymmetry, a relative macrocephaly, a characteristic triangular face and further dysmorphisms. In about 50% of patients genetic/epigenetic alterations can be detected: >38% of patients show a hypomethylation of the IGF2/H19 imprinting region in 11p15, additional 10% carry a maternal uniparental disomy of chromosome 7. In single cases, cytogenetic aberrations can be detected. Nevertheless, there still remain 50% of SRS patients without known genetic/epigenetic alterations. To find out whether submicroscopic imbalances contribute to the aetiology of SRS we screened 20 idiopathic SRS patients with the Affymetrix GeneChip(R) Human Mapping 500 K array set. Apart from known apathogenic copy number variations (CNVs) we identified one patient with a 12q14 microdeletion. The 12q14 microdeletion syndrome is characterised by dwarfism but it additionally includes mental retardation and osteopoikilosis. The deletion in our patient is smaller than those in the 12q14 microdeletion carriers but it also affects the LEMD3 and the HMGA2 genes. LEMD3 haploinsufficiency and point mutations have been previously associated with osteopoikilosis but radiographs of our patient at the age of 16 years did not reveal any hint for osteopoikilosis lesions. Haploinsufficiency of HMGA2 is probably responsible for aberrant growth in 12q14 microdeletion syndrome. However, we excluded a general role of HMGA2 mutations for SRS by sequencing of 20 idiopathic patients. In conclusion, our results exclude a common cryptic chromosomal imbalance in idiopathic SRS patients but show that chromosomal aberrations are relevant in this disease. Thus molecular karyotyping is indicated in SRS and should be included in the diagnostic algorithm.

Silver-Russell syndrome (SRS) is a heterogeneous disorder associated with intrauterine and postnatal growth restriction, body asymmetry, a relative macrocephaly, a characteristic triangular face and further dysmorphisms. In about 50% of patients genetic/epigenetic alterations can be detected: >38% of patients show a hypomethylation of the IGF2/H19 imprinting region in 11p15, additional 10% carry a maternal uniparental disomy of chromosome 7. In single cases, cytogenetic aberrations can be detected. Nevertheless, there still remain 50% of SRS patients without known genetic/epigenetic alterations. To find out whether submicroscopic imbalances contribute to the aetiology of SRS we screened 20 idiopathic SRS patients with the Affymetrix GeneChip(R) Human Mapping 500 K array set. Apart from known apathogenic copy number variations (CNVs) we identified one patient with a 12q14 microdeletion. The 12q14 microdeletion syndrome is characterised by dwarfism but it additionally includes mental retardation and osteopoikilosis. The deletion in our patient is smaller than those in the 12q14 microdeletion carriers but it also affects the LEMD3 and the HMGA2 genes. LEMD3 haploinsufficiency and point mutations have been previously associated with osteopoikilosis but radiographs of our patient at the age of 16 years did not reveal any hint for osteopoikilosis lesions. Haploinsufficiency of HMGA2 is probably responsible for aberrant growth in 12q14 microdeletion syndrome. However, we excluded a general role of HMGA2 mutations for SRS by sequencing of 20 idiopathic patients. In conclusion, our results exclude a common cryptic chromosomal imbalance in idiopathic SRS patients but show that chromosomal aberrations are relevant in this disease. Thus molecular karyotyping is indicated in SRS and should be included in the diagnostic algorithm.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:08 University Research Priority Programs > Systems Biology / Functional Genomics
07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2010
Deposited On:05 Feb 2010 10:04
Last Modified:05 Apr 2016 13:49
Publisher:BMJ Publishing Group
ISSN:0022-2593
Publisher DOI:10.1136/jmg.2009.070052
PubMed ID:19762329
Permanent URL: http://doi.org/10.5167/uzh-28718

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