María José Aparisi

Instituto de Investigación Sanitaria La Fe

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José M. Millán

Instituto de Investigación Sanitaria La Fe

Elena Aller

Centre for Biomedical Network Research on Rare Diseases

Teresa Jaijo

Centre for Biomedical Network Research on Rare Diseases

Gema García‐García

Instituto de Investigación Sanitaria La Fe

Laia Pedrola

Hospital Universitari i Politècnic La Fe

Carmen Ayuso

Centre for Biomedical Network Research on Rare Diseases

Marina Martínez-Matilla

Igenomix

Regina Rodrigo

Centre for Biomedical Network Research on Rare Diseases

Inés Calabria

Instituto de Medicina Genómica

M. Díaz-Llopis

Hospital Universitari i Politècnic La Fe

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Hospital Universitari i Politècnic La Fe

Instituto de Investigación Sanitaria La Fe

Leitat Technological Center

Centre for Biomedical Network Research on Rare Diseases

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Universitat de València

Instituto de Investigación de Enfermedades Raras

Hospital Clínico Universitario de Valencia

Centro de Investigacion Principe Felipe

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Microarray-Based Mutation Analysis of 183 Spanish Families with Usher Syndrome

Investigative Ophthalmology & Visual Science (2010)

Teresa Jaijo Elena Aller Gema García‐García María José Aparisi Sara Bernal

Purpose.: The purpose of this study was to test the ability of the genotyping microarray for Usher syndrome (USH) to identify the mutations responsible for the disease in a cohort of 183 patients with USH. Methods.: DNA from 183 patients with Usher syndrome from the Spanish population was analyzed using a genotyping microarray containing 429 previously identified disease-associated variants in eight USH genes. Mutations detected by the array were confirmed by direct sequencing. Haplotype analysis was also performed in families carrying common Spanish mutations. Results.: The genotyping microarray identified 43 different variants, divided into 32 disease causative and 11 probably nonpathologic. Mutations were detected in 62 patients with USH (33.9%). According to the clinical classification of patients, pathologic variants were detected in 31.4% patients with USH1, 39.4% of with USH2, 22.2% with USH3 and 15.8% with unclassified Usher syndrome. Ninety-seven pathologic alleles were detected, corresponding to 26.5% of expected alleles. The USH2A mutations p.C3267R and p.T3571M were revealed as common in the Spanish population, and two major haplotypes linked to these mutations were observed. Conclusions.: The genotyping microarray is a robust, low-cost, rapid technique that is effective for the genetic study of patients with USH. However, it also indicates variants of unclear pathologic nature and detection failures have also been observed. Results must be confirmed by direct sequencing to avoid misdiagnosis, and continuous updates of the microarray should be performed to increase the efficiency and rate of detection of mutations.

Usher syndrome

10.1167/iovs.09-4085

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Citations (60)

The Value of Multislice Computed Tomography in the Diagnosis of Elbow Fractures

Seminars in Musculoskeletal Radiology (2013)

María José Aparisi Francisco Aparisi

Within the sports pathology it is vital the functional recovery of the lesions. To achieve this goal it is necessary very precise anatomical information. The elbow region is made up of three bones that together they have a complex relationship. Range of motion is wide and is thanks to the form of their components. To obtain precise information we need complex imaging techniques that allow us to avoid overlaps that show conventional radiology. Thanks to the development of CT multislices we have a high precision tool. Following the classification of the AO Foundation describes all types of fracture and provides images with 3D reconstruciton which allows you to schedule surgery the surgeon with a degree of prior information that approximates the excellence.

Multislice computed tomography

Multislice

Excellence

10.1055/s-0033-1360664

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Great clinical variability of Nance Horan syndrome due to deleterious NHS mutations in two unrelated Spanish families

Ophthalmic Genetics (2019)

Víctor Hernández Isabel Pascual-Camps María José Aparisi Marina Martínez-Matilla Francisco Martı́nez

Background: Nance-Horan syndrome (NHS) is an X-linked rare congenital disorder caused by mutations in the NHS gene. Clinical manifestations include congenital cataracts, facial and dental dysmorphism and, in some cases, intellectual disability. The aim of the present work was to identify the genetic cause of this disease in two unrelated Spanish NHS families and to determine the relative involvement of this gene in the pathogenesis.Materials and methods: Four members of a two-generation family, three males and one female (Family 1), and seven members of a three-generation family, two males and five females (Family 2) were recruited and their index cases were screened for mutations in the NHS gene and 26 genes related with ocular congenital anomalies by NGS (Next Generation Sequencing).Results: Two pathogenic variants were found in the NHS gene: a nonsense mutation (p.Arg373X) and a frameshift mutation (p.His669ProfsX5). These mutations were found in the two unrelated NHS families with different clinical manifestations.Conclusions: In the present study, we identified two truncation mutations (one of them novel) in the NHS gene, associated with NHS. Given the wide clinical variability of this syndrome, NHS may be difficult to detect in individuals with subtle clinical manifestations or when congenital cataracts are the primary clinical manifestation which makes us suspect that it can be underdiagnosed. Combination of genetic studies and clinical examinations are essential for the clinical diagnosis optimization.

Nonsense

Nonsense mutation

10.1080/13816810.2019.1692362

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Study of USH1 Splicing Variants through Minigenes and Transcript Analysis from Nasal Epithelial Cells

PLoS ONE (2013)

María José Aparisi Gema García‐García Elena Aller María Dolores Sequedo Cristina Martínez-Fernández de la Cámara

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital profound deafness, vestibular areflexia and prepubertal retinitis pigmentosa. The first purpose of this study was to determine the pathologic nature of eighteen USH1 putative splicing variants found in our series and their effect in the splicing process by minigene assays. These variants were selected according to bioinformatic analysis. The second aim was to analyze the USH1 transcripts, obtained from nasal epithelial cells samples of our patients, in order to corroborate the observed effect of mutations by minigenes in patient's tissues. The last objective was to evaluate the nasal ciliary beat frequency in patients with USH1 and compare it with control subjects. In silico analysis were performed using four bioinformatic programs: NNSplice, Human Splicing Finder, NetGene2 and Spliceview. Afterward, minigenes based on the pSPL3 vector were used to investigate the implication of selected changes in the mRNA processing. To observe the effect of mutations in the patient's tissues, RNA was extracted from nasal epithelial cells and RT-PCR analyses were performed. Four MYO7A (c.470G>A, c.1342_1343delAG, c.5856G>A and c.3652G>A), three CDH23 (c.2289+1G>A, c.6049G>A and c.8722+1delG) and one PCDH15 (c.3717+2dupTT) variants were observed to affect the splicing process by minigene assays and/or transcripts analysis obtained from nasal cells. Based on our results, minigenes are a good approach to determine the implication of identified variants in the mRNA processing, and the analysis of RNA obtained from nasal epithelial cells is an alternative method to discriminate neutral Usher variants from those with a pathogenic effect on the splicing process. In addition, we could observe that the nasal ciliated epithelium of USH1 patients shows a lower ciliary beat frequency than control subjects.

Minigene

10.1371/journal.pone.0057506

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Citations (23)

6113-6. SUSTITUCIÓN EN RBM20 AFECTANDO EL SPLICING, ¿PRIMERA FAMILIA QUE DEMUESTRA LA PATOGENICIDAD DE ESTE TIPO DE ALTERACIONES?

Revista Española de Cardiología (2024)

Guillermo García Jorge Llau García Esther Zorio Grima Sara Huélamo Montoro Natalia Ortiz

10.1016/s0300-8932(25)00407-5

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Novel mutations in the USH1C gene in Usher syndrome patients.

PubMed (2010)

María José Aparisi Gema García‐García Teresa Jaijo Regina Rodrigo Claudio Graziano

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by severe-profound sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia. To date, five USH1 genes have been identified. One of these genes is Usher syndrome 1C (USH1C), which encodes a protein, harmonin, containing PDZ domains. The aim of the present work was the mutation screening of the USH1C gene in a cohort of 33 Usher syndrome patients, to identify the genetic cause of the disease and to determine the relative involvement of this gene in USH1 pathogenesis in the Spanish population.Thirty-three patients were screened for mutations in the USH1C gene by direct sequencing. Some had already been screened for mutations in the other known USH1 genes (myosin VIIA [MYO7A], cadherin-related 23 [CDH23], protocadherin-related 15 [PCDH15], and Usher syndrome 1G [USH1G]), but no mutation was found.Two novel mutations were found in the USH1C gene: a non-sense mutation (p.C224X) and a frame-shift mutation (p.D124TfsX7). These mutations were found in a homozygous state in two unrelated USH1 patients.In the present study, we detected two novel pathogenic mutations in the USH1C gene. Our results suggest that mutations in USH1C are responsible for 1.5% of USH1 disease in patients of Spanish origin (considering the total cohort of 65 Spanish USH1 patients since 2005), indicating that USH1C is a rare form of USH in this population.

Usher syndrome

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Citations (7)

Additional file 3: of Precision medicine in relapsed or refractory pediatric solid tumors: a collaborative Spanish initiative

Figshare (2019)

Pablo Gargallo Jaime Font de Mora Pablo Berlanga Inés Calabria Margarita Llavador

Reference database. (XLSX 21 kb)

Refractory (planetary science)

Solid tumor

10.6084/m9.figshare.8480039

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Citations (0)

Two novel disease-causing mutations in the CLRN1 gene in patients with Usher syndrome type 3.

PubMed (2012)

Gema García‐García María José Aparisi Regina Rodrigo María Dolores Sequedo Carmen Espinós

To identify the genetic defect in Spanish families with Usher syndrome (USH) and probable involvement of the CLRN1 gene.

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Identification of Large Rearrangements of thePCDH15Gene by Combined MLPA and a CGH: Large Duplications Are Responsible for Usher Syndrome

Investigative Ophthalmology & Visual Science (2010)

Elena Aller Teresa Jaijo Gema García‐García María José Aparisi David Blesa

PCDH15, encoding protocadherin 15, is mutated in Usher syndrome type 1F (USH1F) patients. Not only point mutations, but also large deletions have been detected within this gene. However, the detection and characterization of gross deletions in the USH1F locus have been difficult. The purpose of the present work was to identify large genomic rearrangements of PCDH15 in a cohort of patients and to accurately identify the location of the junction breakpoints of the detected rearrangements.A PCDH15 MLPA (multiplex ligation-dependent probe amplification) commercial kit was used, combined with a customized oligonucleotide array-based CGH analysis (aCGH), containing almost 20,000 probes tiling the nonrepetitive sequence of the PCDH15 gene.Two large intragenic rearrangements were identified-one deletion of 55 kb and one direct duplication of 82 kb-in 3 (13%) families from a cohort of 23 USH cases. The patients had been screened for mutations in the five known USH1 genes and were found to carry one or none of the pathogenic mutations in PCDH15. The exact breakpoints of both rearrangements were identified.This is the first time that large duplications have been associated with Usher syndrome. USH patients have not been extensively tested for large genomic rearrangements such as duplications and deletions. This type of mutation easily escapes detection by traditional PCR-basedThus, a combination of PCR-based mutation screening, together with deletion and duplication analysis, is mandatory for the accurate screening of the PCDH15 gene in Usher patients.

Breakpoint

Comparative genomic hybridization

10.1167/iovs.10-5359

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Citations (30)

New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy

PLoS ONE (2018)

Sarah Moreau-Le Lan Elena Aller Inés Calabria Lola González-Tarancón C. C. GAY

Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different genes have been associated with NM. The most frequently responsible genes are NEB (50% of cases) and ACTA1 (15–25% of cases). In this report all known NM related genes were screened by Next Generation Sequencing in five Spanish patients in order to genetically confirm the clinical and histological diagnosis of NM. Four mutations in NEB (c.17779_17780delTA, c.11086A>C, c.21076C>T and c.2310+5G>A) and one mutation in ACTA1 (c.871A>T) were found in four patients. Three of the four mutations in NEB were novel. A cDNA sequencing assay of the novel variants c.17779_17780delTA, c.11086A>C and c.2310+5G>A revealed that the intronic variant c.2310+5G>A affected the splicing process. Mutations reported here could help clinicians and geneticists in NM diagnosis.

Nemaline myopathy

Nebulin

Compound heterozygosity

10.1371/journal.pone.0207296

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Citations (9)