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Papers by Violetta Anastasiadou

Research paper thumbnail of Corresponding author

Familial adenomatous polyposis (FAP) and Hereditary Non Polyposis Syndrome (HNPCC) are the two co... more Familial adenomatous polyposis (FAP) and Hereditary Non Polyposis Syndrome (HNPCC) are the two commonest familial syndromes that predispose to colorectal cancer. FAP is caused by mutations in the Adenomatous Polyposis Coli (APC) tumour suppressor gene that has a high penetrance. The disease is characterized by the occurrence of hundreds to thousands of colorectal polyps, which if left untreated give rise to colorectal cancer. On the other hand HNPCC is characterized by development of colorectal cancer at an early age, in the absence of polyps. This syndrome is caused by germline mutations in the mismatch repair genes (hMLH1, hMSH2, hMSH6, hPMS1 and hMSH2). In Cyprus there are no molecular data available as yet, on families with FAP or HNPCC. This work presents the results of APC analysis in our population for the first time. The APC gene was analysed in 33 DNA samples from 20 individuals belonging to 4 FAP families and 13 patients with sporadic polyposis. We identified 3 truncating ...

Research paper thumbnail of Chromosomal imbalance letter 9 Mb familial duplication in chromosome band Xp22.2e22.13 associated with mental retardation, hypotonia and developmental delay, scoliosis, cardiovascular problems and mild dysmorphic facial features

We report on a family with syndromic X-linked mental retardation (XLMR) caused by an Xp22.2e22.13... more We report on a family with syndromic X-linked mental retardation (XLMR) caused by an Xp22.2e22.13 duplication. This family consists of a carrier mother and daughter and four affected sons, presenting with mental retardation, developmental delay, cardiovascular problems and mild dysmorphic facial features. Female carriers have normal intelligence and some common clinical features, as well as different clinical abnormalities. Cytogenetic analysis of the mother showed an Xp22.2 duplication which was passed to all her offspring. Fluorescence In Situ Hybridization (FISH) using whole chromosome paint and Bacterial Artificial Chromosome (BAC) clones covering Xp22.12eXp22.3 region, confirmed the X chromosome origin and the size of the duplication. Two different targeted microarray methodologies were used for breakpoint confirmation, resulting in the localization of the duplication to approximately 9.75e18.98 Mb. Detailed description of such rare duplications provides valuable data for the i...

Research paper thumbnail of Patient report

Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive diaphyseal dysplasia a... more Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive diaphyseal dysplasia as a result of mutations in the transforming growth factor gene TGFbeta1 on chromosome 19q13.1-q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty, and hypogonadotrophic hypogonadism may be present. Methods: Genetic analysis of the TGFbeta1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia, and menstrual irregularity. Results: The patient responded well to prednisone 5 mg/kg/day, as well as calcium and vitamin D supplements. Conclusions: The role of p.R218C in TGFbeta1 on the mechanism of the disease, and the complications of it in bones and endocrine glands, remains unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease are important for future treatment options and a better quali...

Research paper thumbnail of The Landscape of Mucopolysaccharidosis in Southern and Eastern European Countries: A Survey from 19 Specialistic Centers

Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defe... more Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the landscape of disease management in the region and understand ERT implementation, with particular reference to MPS IVA.Results: 19 experts from 14 Southern and Eastern European co...

Research paper thumbnail of An unusual combination of an atypical maternally inherited novel 0.3 Mb deletion in Williams-Beuren region and a de novo 22q11.21 microduplication in an infant with supravalvular aortic stenosis

European Journal of Medical Genetics, 2020

Research paper thumbnail of Molecular analysis of Cypriot families with aniridia reveals a novel PAX6 mutation

Molecular medicine reports, 2018

The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17... more The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17 affected individuals from six families from Cyprus. Each proband was initially evaluated for copy number variants at the PAX6 locus and subsequently underwent PAX6 mutation screening. Sequence analysis of FOXC1 and PITX2 was performed in patients who did not carry a PAX6 mutation. The most common clinical features in the group of aniridia patients associated with aniridia were nystagmus, cataracts and glaucoma. PAX6 pathogenic mutations were identified in five out of six families (a diagnostic yield of 84%). Previously reported pathogenic mutations in PAX6 were identified in four families, which comprise p.R203*, p.R240* and p.R317*. In addition, a novel pathogenic variant (p.E220Gfs*23) was identified in a single family. No pathogenic mutations were detected in PAX6, FOXC1 or PITX2 in the only patient with a sporadic form of aniridia‑like phenotype, confirming the genetic heterogeneity...

Research paper thumbnail of Identification of a novel 15.5 kb SHOX deletion associated with marked intrafamilial phenotypic variability and analysis of its molecular origin

Journal of Genetics, 2016

Research paper thumbnail of A novel HCFC1 variant in male siblings with intellectual disability and microcephaly in the absence of cobalamin disorder

Research paper thumbnail of A case of Camurati-Engelmann disease with endocrine complications due to a missense mutation of the TGFB1 gene

Research paper thumbnail of Haploinsufficiency of the miR-873/miR-876 microRNA cluster is associated with craniofacial abnormalities

Research paper thumbnail of The interface between medically assisted reproduction and genetics: Technical, social, ethical and legal issues

Research paper thumbnail of The BRCA1 Variant p.Ser36Tyr Abrogates BRCA1 Protein Function and Potentially Confers a Moderate Risk of Breast Cancer

Research paper thumbnail of P10 Preimplantation genetic diagnosis for the first family with Tay–Sachs disease in Cyprus

Reproductive BioMedicine Online, 2012

Research paper thumbnail of High Frequency of 35delG GJB2 Mutation and Absence of del(GJB6-D13S1830) in Greek Cypriot Patients with Nonsyndromic Hearing Loss

Research paper thumbnail of 263.4 kb deletion within the TCF4 gene consistent with Pitt–Hopkins syndrome, inherited from a mosaic parent with normal phenotype

European Journal of Medical Genetics, 2013

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental genetic disorder, remaining under-diagn... more Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental genetic disorder, remaining under-diagnosed due to similarities with other known genetic syndromes. It is mainly characterized by severe intellectual disability, overbreathing, a typical facial gestalt, tendency to epilepsy and is caused by TCF4 haploinsufficiency. We report on a 14-year old boy, born to healthy non-consanguineous parents, with a PTHS spectrum phenotype, presenting with moderate to severe developmental delay, severe speech delay and facial dysmorphism. Genetic investigation using array-based comparative genomic hybridization (array-CGH) with a 400K custom array, revealed a 263.4 kb deletion within the TCF4 gene, removing exons 4-9. Parental array-CGH analysis was also performed, indicating paternal mosaicism for the same deletion. The mosaicism was confirmed by Quantitative Real-Time PCR. The current report describes a new TCF4 deletion associated with a PTHS phenotype. Moreover, it is the first case to our knowledge, where such a deletion is shown to be inherited from a clinically unaffected mosaic parent. Our results highlight the importance of parental testing in this setting for more accurate and focused prenatal diagnosis. The level and tissue-specificity of mosaicism in the father would be an interesting direction for further studies.

Research paper thumbnail of Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus

Research paper thumbnail of Determination of the carrier frequency of the common GJB2 (connexin-26) 35delG mutation in the Greek Cypriot population

International Journal of Pediatric Otorhinolaryngology, 2006

Research paper thumbnail of PR23 BRCA mutations and breast cancer in young women in Cyprus

Research paper thumbnail of The Mutational Spectrum of Lynch Syndrome in Cyprus

Research paper thumbnail of Screening of 50 Cypriot Patients with Autism Spectrum Disorders or Autistic Features Using 400K Custom Array-CGH

BioMed Research International, 2013

Autism spectrum disorders (ASDs) comprise a distinct entity of neurodevelopmental disorders with ... more Autism spectrum disorders (ASDs) comprise a distinct entity of neurodevelopmental disorders with a strong genetic component. Despite the identification of several candidate genes and causative genomic copy number variations (CNVs), the majority of ASD cases still remain unresolved. We have applied microarray-based comparative genomic hybridization (array-CGH) using Agilent 400K custom array in the first Cyprus population screening for identification of ASD-associated CNVs. A cohort of 50 ASD patients (G1), their parents (G2), 50 ethnically matched normal controls (G3), and 80 normal individuals having children with various developmental and neurological conditions (G4) were tested. As a result, 14 patients were found to carry 20 potentially causative aberrations, two of which werede novo. Comparison of the four population groups revealed an increased rate of rare disease-associated variants in normal parents of children with autism. The above data provided additional evidence, suppo...

Research paper thumbnail of Corresponding author

Familial adenomatous polyposis (FAP) and Hereditary Non Polyposis Syndrome (HNPCC) are the two co... more Familial adenomatous polyposis (FAP) and Hereditary Non Polyposis Syndrome (HNPCC) are the two commonest familial syndromes that predispose to colorectal cancer. FAP is caused by mutations in the Adenomatous Polyposis Coli (APC) tumour suppressor gene that has a high penetrance. The disease is characterized by the occurrence of hundreds to thousands of colorectal polyps, which if left untreated give rise to colorectal cancer. On the other hand HNPCC is characterized by development of colorectal cancer at an early age, in the absence of polyps. This syndrome is caused by germline mutations in the mismatch repair genes (hMLH1, hMSH2, hMSH6, hPMS1 and hMSH2). In Cyprus there are no molecular data available as yet, on families with FAP or HNPCC. This work presents the results of APC analysis in our population for the first time. The APC gene was analysed in 33 DNA samples from 20 individuals belonging to 4 FAP families and 13 patients with sporadic polyposis. We identified 3 truncating ...

Research paper thumbnail of Chromosomal imbalance letter 9 Mb familial duplication in chromosome band Xp22.2e22.13 associated with mental retardation, hypotonia and developmental delay, scoliosis, cardiovascular problems and mild dysmorphic facial features

We report on a family with syndromic X-linked mental retardation (XLMR) caused by an Xp22.2e22.13... more We report on a family with syndromic X-linked mental retardation (XLMR) caused by an Xp22.2e22.13 duplication. This family consists of a carrier mother and daughter and four affected sons, presenting with mental retardation, developmental delay, cardiovascular problems and mild dysmorphic facial features. Female carriers have normal intelligence and some common clinical features, as well as different clinical abnormalities. Cytogenetic analysis of the mother showed an Xp22.2 duplication which was passed to all her offspring. Fluorescence In Situ Hybridization (FISH) using whole chromosome paint and Bacterial Artificial Chromosome (BAC) clones covering Xp22.12eXp22.3 region, confirmed the X chromosome origin and the size of the duplication. Two different targeted microarray methodologies were used for breakpoint confirmation, resulting in the localization of the duplication to approximately 9.75e18.98 Mb. Detailed description of such rare duplications provides valuable data for the i...

Research paper thumbnail of Patient report

Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive diaphyseal dysplasia a... more Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive diaphyseal dysplasia as a result of mutations in the transforming growth factor gene TGFbeta1 on chromosome 19q13.1-q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty, and hypogonadotrophic hypogonadism may be present. Methods: Genetic analysis of the TGFbeta1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia, and menstrual irregularity. Results: The patient responded well to prednisone 5 mg/kg/day, as well as calcium and vitamin D supplements. Conclusions: The role of p.R218C in TGFbeta1 on the mechanism of the disease, and the complications of it in bones and endocrine glands, remains unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease are important for future treatment options and a better quali...

Research paper thumbnail of The Landscape of Mucopolysaccharidosis in Southern and Eastern European Countries: A Survey from 19 Specialistic Centers

Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defe... more Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the landscape of disease management in the region and understand ERT implementation, with particular reference to MPS IVA.Results: 19 experts from 14 Southern and Eastern European co...

Research paper thumbnail of An unusual combination of an atypical maternally inherited novel 0.3 Mb deletion in Williams-Beuren region and a de novo 22q11.21 microduplication in an infant with supravalvular aortic stenosis

European Journal of Medical Genetics, 2020

Research paper thumbnail of Molecular analysis of Cypriot families with aniridia reveals a novel PAX6 mutation

Molecular medicine reports, 2018

The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17... more The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17 affected individuals from six families from Cyprus. Each proband was initially evaluated for copy number variants at the PAX6 locus and subsequently underwent PAX6 mutation screening. Sequence analysis of FOXC1 and PITX2 was performed in patients who did not carry a PAX6 mutation. The most common clinical features in the group of aniridia patients associated with aniridia were nystagmus, cataracts and glaucoma. PAX6 pathogenic mutations were identified in five out of six families (a diagnostic yield of 84%). Previously reported pathogenic mutations in PAX6 were identified in four families, which comprise p.R203*, p.R240* and p.R317*. In addition, a novel pathogenic variant (p.E220Gfs*23) was identified in a single family. No pathogenic mutations were detected in PAX6, FOXC1 or PITX2 in the only patient with a sporadic form of aniridia‑like phenotype, confirming the genetic heterogeneity...

Research paper thumbnail of Identification of a novel 15.5 kb SHOX deletion associated with marked intrafamilial phenotypic variability and analysis of its molecular origin

Journal of Genetics, 2016

Research paper thumbnail of A novel HCFC1 variant in male siblings with intellectual disability and microcephaly in the absence of cobalamin disorder

Research paper thumbnail of A case of Camurati-Engelmann disease with endocrine complications due to a missense mutation of the TGFB1 gene

Research paper thumbnail of Haploinsufficiency of the miR-873/miR-876 microRNA cluster is associated with craniofacial abnormalities

Research paper thumbnail of The interface between medically assisted reproduction and genetics: Technical, social, ethical and legal issues

Research paper thumbnail of The BRCA1 Variant p.Ser36Tyr Abrogates BRCA1 Protein Function and Potentially Confers a Moderate Risk of Breast Cancer

Research paper thumbnail of P10 Preimplantation genetic diagnosis for the first family with Tay–Sachs disease in Cyprus

Reproductive BioMedicine Online, 2012

Research paper thumbnail of High Frequency of 35delG GJB2 Mutation and Absence of del(GJB6-D13S1830) in Greek Cypriot Patients with Nonsyndromic Hearing Loss

Research paper thumbnail of 263.4 kb deletion within the TCF4 gene consistent with Pitt–Hopkins syndrome, inherited from a mosaic parent with normal phenotype

European Journal of Medical Genetics, 2013

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental genetic disorder, remaining under-diagn... more Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental genetic disorder, remaining under-diagnosed due to similarities with other known genetic syndromes. It is mainly characterized by severe intellectual disability, overbreathing, a typical facial gestalt, tendency to epilepsy and is caused by TCF4 haploinsufficiency. We report on a 14-year old boy, born to healthy non-consanguineous parents, with a PTHS spectrum phenotype, presenting with moderate to severe developmental delay, severe speech delay and facial dysmorphism. Genetic investigation using array-based comparative genomic hybridization (array-CGH) with a 400K custom array, revealed a 263.4 kb deletion within the TCF4 gene, removing exons 4-9. Parental array-CGH analysis was also performed, indicating paternal mosaicism for the same deletion. The mosaicism was confirmed by Quantitative Real-Time PCR. The current report describes a new TCF4 deletion associated with a PTHS phenotype. Moreover, it is the first case to our knowledge, where such a deletion is shown to be inherited from a clinically unaffected mosaic parent. Our results highlight the importance of parental testing in this setting for more accurate and focused prenatal diagnosis. The level and tissue-specificity of mosaicism in the father would be an interesting direction for further studies.

Research paper thumbnail of Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus

Research paper thumbnail of Determination of the carrier frequency of the common GJB2 (connexin-26) 35delG mutation in the Greek Cypriot population

International Journal of Pediatric Otorhinolaryngology, 2006

Research paper thumbnail of PR23 BRCA mutations and breast cancer in young women in Cyprus

Research paper thumbnail of The Mutational Spectrum of Lynch Syndrome in Cyprus

Research paper thumbnail of Screening of 50 Cypriot Patients with Autism Spectrum Disorders or Autistic Features Using 400K Custom Array-CGH

BioMed Research International, 2013

Autism spectrum disorders (ASDs) comprise a distinct entity of neurodevelopmental disorders with ... more Autism spectrum disorders (ASDs) comprise a distinct entity of neurodevelopmental disorders with a strong genetic component. Despite the identification of several candidate genes and causative genomic copy number variations (CNVs), the majority of ASD cases still remain unresolved. We have applied microarray-based comparative genomic hybridization (array-CGH) using Agilent 400K custom array in the first Cyprus population screening for identification of ASD-associated CNVs. A cohort of 50 ASD patients (G1), their parents (G2), 50 ethnically matched normal controls (G3), and 80 normal individuals having children with various developmental and neurological conditions (G4) were tested. As a result, 14 patients were found to carry 20 potentially causative aberrations, two of which werede novo. Comparison of the four population groups revealed an increased rate of rare disease-associated variants in normal parents of children with autism. The above data provided additional evidence, suppo...