Journal Article

Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype

Friedrich Asmus, Lena Elisabeth Hjermind, Erik Dupont, Janine Wagenstaller, Edda Haberlandt, Marita Munz, Tim M. Strom and Thomas Gasser

in Brain

Published on behalf of The Guarantors of Brain

Volume 130, issue 10, pages 2736-2745
Published in print October 2007 | ISSN: 0006-8950
Published online October 2007 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awm209
Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype

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Myoclonus–dystonia (M–D, DYT11) is a dystonia plus syndrome characterized by brief myoclonic jerks predominantly of neck and upper limbs in combination with focal or segmental dystonia. It is caused by heterozygous mutations of the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21.3. We present three patients with heterozygous large deletions in the 7q21.13-21.3 region. By quantitative analysis of single nucleotide polymorphism (SNP) oligonucleotide arrays, the deletion size was determined to range from 1.63 to 8.78 Mb. All deletions contained the maternally imprinted SGCE gene and up to 43 additional neighbouring genes. Two of the patients presented with typical M–D, whereas one paediatric patient with split-hand/split-foot malformation and sensorineural hearing loss (SHFM1D, OMIM 220600) had not developed M–D at the age of 9 years. This patient had the largest deletion of 8.78 Mb (7q21.13-21.3) containing also SHFM1, DLX6 and DLX5, which had been previously shown to be deleted in SHFM1D. In two patients, the deletions removed the paternal allele of the KRIT1 gene, which is a major cause of cavernous cerebral malformations type 1 (CCM1). Only the adult patient showed asymptomatic cavernous cerebral malformations on cranial MRI, underlining age-dependent penetrance and haploinsufficiency as pivotal features of patients with KRIT1 mutations. All three deletions contained the COL1A2 gene. In contrast to dominant negative point mutations, which cause osteogenesis imperfecta with bone fractures, haploinsufficiency of COL1A2 resulted only in subtle symptoms like recurrent joint subluxation or hypodontia. Assessing copy number variations by SNP arrays is an easy and reliable technique to delineate the size of human interstitial deletions. It will therefore become a standard technique to study patients, in whom heterozygous whole gene deletions are detected and information on neighbouring deleted genes is required for comprehensive genetic counselling and clinical management.

Keywords: 7q21 deletion; myoclonus–dystonia; SCGE; cavernous cerebral malformations; KRIT1

Journal Article.  5175 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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