Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1

Fontalba, Ana; Fernández-Luna, José L.; Zarrabeitia, Roberto; Recio-Poveda, Lucía; Albiñana, Virginia; Ojeda-Fernández, Luisa; Bernabéu, Carmelo; Alcaraz, Luís A.; Botella, Luisa María

doi:10.1186/1471-2350-14-121

Cited by 6 publications

(6 citation statements)

References 32 publications

(38 reference statements)

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“…HHT is a monogenic disease; however there are a wide variety of possible mutations, making diagnosis difficult. For example, there are pathologic alterations in introns and at the promoter as well as many kinds of deletions/insertions in the gene [32,33]. Significantly, during the period of study, the Unit carried out preimplantation embryonic diagnoses (PGD) [34] for three couples which allowed them to have disease-free children.…”

Section: Probable Information Biasesmentioning

confidence: 99%

Epidemiology of Hereditary Haemorrhagic Telangiectasia (HHT) in Spain

Puente¹,

Bueno²,

Salcedo³

et al. 2016

Hereditary Genet

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Aim: To describe epidemiological characteristics of a wide cohort of Spanish patients with hereditary hemorrhagic telangiectasia (HHT)/ Rendu-Osler-Weber disease. Methods and Results: Between 1 January 2002 and 31 December 2013, 667 Spanish patients with suspected HHT were evaluated in the reference HHT Unit in Hospital Sierrallana and 449 were diagnosed by clinical Curaçao criteria and/or genetic test. The diagnostic sensitivity of Curaçao clinical criteria in the population studied was 94.59%. Prevalence was 1:5,936 people and lethality rate of 0.16%. Type 2 HHT was the most prevalent and in total 147 different mutations was identified. Epistaxis was the most prevalent symptom (96.88% of cases) while 95.18% of patients showed typical telangiectasias. Pulmonary involvement was present in 28.25% of patients (by computed tomography) mainly in women and HHT1 cases while liver infection was more prevalent in HHT2 cases. Brain involvement was disclosed in 28.35% of cases. Telangiectasias in conjuctival mucose were very frequent mainly in HHT1 elderly patients. Conclusion: This is the first representative series of epidemiological data on a non-previously evaluated population, showing results about prevalence, genetic distribution and organ infection and disclosing new observations that can help guide the diagnostic and screening procedures for these patients.

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Section: Probable Information Biasesmentioning

confidence: 99%

Epidemiology of Hereditary Haemorrhagic Telangiectasia (HHT) in Spain

Puente¹,

Bueno²,

Salcedo³

et al. 2016

Hereditary Genet

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“…18 Deletions involving ENG in a subset of HHT1 patients have been reported, suggesting that haploinsufficiency of ENG gene causes HHT1. [19][20][21]…”

Section: Engmentioning

confidence: 99%

Epilepsy and Other Symptoms Associated with Chromosome 9q34.11 Microdeletion

Akiyama

Yamamoto

2015

J Pediatr Epilepsy

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Early-onset epileptic encephalopathy (EOEE) is a devastating condition in early childhood that often results in severe and permanent cognitive and motor deficit. Advances in genetics have unveiled many genes involved in EOEE. STXBP1 and SPTAN1 genes, of interest, are mapped to the same chromosomal region 9q34.11. Microdeletions involving this 9q34.11 region can lead to variable clinical phenotypes depending on the range of, and the genes within, the deletion. In this region, STXBP1, SPTAN1, ENG, and TOR1A genes seem to be dosage-sensitive. LMX1B, which is mapped to 9q33.3 and is closely located to the above four genes, could be also involved in the deletion. Twenty cases with deletions involving 9q34.11, including our own case in this article, have been reported in the literature. STXBP1 seems to cause epilepsy, often EOEE, and intellectual disability. SPTAN1 appears to be linked with hypomyelination and hypoplasia of various brain regions, especially corpus callosum, intellectual disability, and abnormal muscle tones. ENG can present with vascular abnormalities including arteriovenous malformation of the lung, liver, and brain. TOR1A can lead to dystonia. LMX1B is responsible for nail and patella malformation. The other deleted genes may add other clinical features such as facial dysmorphism and anomalies of other multiple organs. Utilizing high-resolution microarray analysis to determine the exact range of deletion will help identify more patients in the future to understand various phenotype of 9q34.11 microdeletion.

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“…The classical Sanger sequencing analysis of genes, including genes found as the main cause for HHT, ENG and ACVRL1/ALK1 and sometimes MADH4/SMAD4 (Figures 2A , B ) is currently the method followed in most genetic diagnosis laboratories, complemented with the MLPA (multiplex ligation-dependent probe amplification) technique for large deletion/insertions of exons. In addition, an array CNV/CGH (copy number variation/comparative genomic hybridization) to detect even larger duplications/deletions was also proposed to complement the previous panel ( Fontalba et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Research on potential biomarkers in hereditary hemorrhagic telangiectasia

et al. 2015

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Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder, involving mutations in two predominant genes known as Endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2), as well as in some less frequent genes, such as MADH4/SMAD4 (JP-HHT) or BMP9/GDF2 (HHT5). The diagnosis of HHT patients currently remains at the clinical level, according to the “Curaçao criteria,” whereas the molecular diagnosis is used to confirm or rule out suspected HHT cases, especially when a well characterized index case is present in the family or in an isolated population. Unfortunately, many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Here, several HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins (vascular endothelial growth factor, transforming growth factor β1, soluble endoglin, angiopoietin-2) and microRNA variants (miR-27a, miR-205, miR-210). On the other hand, differential HHT gene expression fingerprinting, next generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.

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Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1

Cited by 6 publications

References 32 publications

Epidemiology of Hereditary Haemorrhagic Telangiectasia (HHT) in Spain

Epidemiology of Hereditary Haemorrhagic Telangiectasia (HHT) in Spain

Epilepsy and Other Symptoms Associated with Chromosome 9q34.11 Microdeletion

Research on potential biomarkers in hereditary hemorrhagic telangiectasia

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