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Stefanova, Margarita
Publications (3 of 3) Show all publications
Parenti, I., Gervasini, C., Pozojevic, J., Wendt, K. S., Watrin, E., Azzollini, J., . . . Kaiser, F. J. (2016). Expanding the clinical spectrum of the "HDAC8-phenotype - implications for molecular diagnostics, counseling and risk prediction. Clinical Genetics, 89(5), 564-573
Open this publication in new window or tab >>Expanding the clinical spectrum of the "HDAC8-phenotype - implications for molecular diagnostics, counseling and risk prediction
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2016 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 89, no 5, p. 564-573Article in journal (Refereed) Published
Abstract [en]

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2016
Keywords
cohesin; Cornelia de Lange syndrome; HDAC8; mosaicism; X-inactivation
National Category
Medical Genetics Psychiatry
Identifiers
urn:nbn:se:liu:diva-128733 (URN)10.1111/cge.12717 (DOI)000374974600007 ()26671848 (PubMedID)
Note

Funding Agencies|German Federal Ministry of Education and Research (BMBF); the Netherlands Organization for Health Research and Development (ZonMW); Agence Nationale de la Recherche (ANR); Schwerpunktprogramm (SPP) fur medizinische Genetik of the University of Lubeck; Spains Ministry of Health-ISCIII [FIS PI12-01318]; Gobierno de Aragon [B20]; Accordo Quadro Universita-Regione Lombardia: SAL31 [17292]

Available from: 2016-06-01 Created: 2016-05-30 Last updated: 2018-03-19
Thunstrom, S., Sodermark, L., Ivarsson, L., Samuelsson, L. & Stefanova, M. (2015). UBE2A Deficiency Syndrome: A Report of Two Unrelated Cases with Large Xq24 Deletions Encompassing UBE2A Gene. American Journal of Medical Genetics. Part A, 167A(1), 204-210
Open this publication in new window or tab >>UBE2A Deficiency Syndrome: A Report of Two Unrelated Cases with Large Xq24 Deletions Encompassing UBE2A Gene
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2015 (English)In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 167A, no 1, p. 204-210Article in journal (Refereed) Published
Abstract [en]

Intragenic mutations of the UBE2A gene, as well as larger deletions of Xq24 encompassing UBE2A have in recent years been associated with a syndromic form of X-linked intellectual disability called UBE2A deficiency syndrome or X-linked intellectual disability type Nascimento (OMIM#300860). Common clinical features in these patients include moderate to severe intellectual disability (ID), heart defects, dysmorphic features such as high forehead, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, wide mouth, myxedematous appearance, hirsutism, onychodystrophy, and genital anomalies. This study investigates clinical and molecular data of two unrelated, affected males with chromosome Xq24 deletions encompassing UBE2A. Both have been followed from birth until two years of age. A review of the previously published patients with deletions encompassing UBE2A is provided. Besides the common features, the two boys show anomalies not previously described, such as retinal coloboma, esophageal atresia with esophageal fistula, long fingers, camptodactyly, clinodactyly, and long broad toes. Analyses of the phenotype-genotype correlations suggest considerable prevalence of heart defects in the group of patients with larger deletions of Xq24 in comparison to the patients having intragenic UBE2A mutations. However, further studies are needed in order to establish statistically reliable phenotype-genotype correlations of this syndrome.

Place, publisher, year, edition, pages
Wiley: 12 months, 2015
Keywords
syndromic intellectual disability type Nascimento; deletion Xq24; UBE2A; heart defects; CXorf56
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-115337 (URN)10.1002/ajmg.a.36800 (DOI)000348843000031 ()25287747 (PubMedID)
Note

Funding Agencies|Ann Mari och Per Ahlqvist Foundation

Available from: 2015-03-13 Created: 2015-03-13 Last updated: 2018-01-11
Yamamoto, T., Wilsdon, A., Joss, S., Isidor, B., Erlandsson, A., Suri, M., . . . Stefanova, M. (2014). An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities. Journal of Human Genetics, 59(6), 300-306
Open this publication in new window or tab >>An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities
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2014 (English)In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 59, no 6, p. 300-306Article in journal (Refereed) Published
Abstract [en]

The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (greater than3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keywords
behavioral abnormality; brain expressed X-linked 3 (BEX3); intellectual disability; interleukin 1 receptor accessory protein-like 2 (IL1RAPL2); microdeletion Xq22; Pelizaeus-Merzbacher disease (PMD); proteolipid protein 1 (PLP1)
National Category
Medical Genetics
Identifiers
urn:nbn:se:liu:diva-109281 (URN)10.1038/jhg.2014.21 (DOI)000338186000002 ()24646727 (PubMedID)
Available from: 2014-08-12 Created: 2014-08-11 Last updated: 2018-01-11Bibliographically approved
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