23 results on '"Rubinato, E."'
Search Results
2. Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment.
- Author
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Jonard, L., Brotto, D., Moreno-Pelayo, M.A., Castillo, I. del, Kremer, H., Pennings, R.J.E., Caria, H., Fialho, G., Boudewyns, A., Camp, G. van, Ołdak, M., Oziębło, D., Deggouj, N., Siati, R.D. De, Gasparini, P., Girotto, G., Verstreken, M., Dossena, S., Roesch, S., Battelino, S., Trebušak Podkrajšek, K., Warnecke, A., Lenarz, T., Lesinski-Schiedat, A., Mondain, M., Roux, A.F., Denoyelle, F., Loundon, N., Serey Gaut, M., Trevisi, P., Rubinato, E., Martini, A., Marlin, S., Jonard, L., Brotto, D., Moreno-Pelayo, M.A., Castillo, I. del, Kremer, H., Pennings, R.J.E., Caria, H., Fialho, G., Boudewyns, A., Camp, G. van, Ołdak, M., Oziębło, D., Deggouj, N., Siati, R.D. De, Gasparini, P., Girotto, G., Verstreken, M., Dossena, S., Roesch, S., Battelino, S., Trebušak Podkrajšek, K., Warnecke, A., Lenarz, T., Lesinski-Schiedat, A., Mondain, M., Roux, A.F., Denoyelle, F., Loundon, N., Serey Gaut, M., Trevisi, P., Rubinato, E., Martini, A., and Marlin, S.
- Abstract
Item does not contain fulltext, The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].
- Published
- 2023
3. The hidden truth of hereditary hearing loss: gaining insight into the genetic basis of non-syndromic mimics.
- Author
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Tesolin, P., Spedicati, B., Morgan, A., Lenarduzzi, S., Rubinato, E., Santin, A., Troian, M., Marangoni, D., and Girotto, G.
- Subjects
GENETICS of deafness ,CONFERENCES & conventions ,HEARING disorders ,MOLECULAR diagnosis - Abstract
Introduction: The definition of a molecular diagnosis for patients affected by hereditary hearing loss (HHL) is significantly hampered by the extreme clinical and genetic heterogeneity that characterise the condition. In particular, peculiar and understudied cases are those of non-syndromic mimics (NSM), meaning patients with particularly mild forms of syndromic HHL or initially presenting isolated deafness and delayed onset of other clinical signs. Material and methods: In the last 18 months, a cohort of 73 apparently non-syndromic Italian HHL patients has been enrolled in the study. All the individuals were negative at GJB2 and STRC genetic tests and underwent whole-exome sequencing, aiming to define a molecular diagnosis and eventually identify NSMs. Results: A molecular diagnosis was provided for 36/73 patients (49.3%), and 12 of them could be classified as NSMs. In detail, two groups of patients could be highlighted: (1) patients presenting subtle additional signs that were missed during the first clinical evaluation and (2) patients whose molecular diagnosis suggests the future development of additional clinical features. In Group 1, two patients were identified, and they carried pathogenic variants within the MITF and GATA3 genes, which are associated with Waardenburg and Barakat syndromes, respectively. As regards Group 2, ten patients were detected, and the involved genes were CDH23 (one patient), USH2A (six patients) and ADGRV1 (three patients). Thus, these results suggest that Usher syndrome type 2 accounts for the vast majority of NSMs (75%). Moreover, these considerations further confirm our previous findings regarding the high prevalence of Usher syndrome type 2 carriers in the Italian population (1: 70). Conclusions: Identifying patients within Group 1 of NSMs highlights the importance of a critical re-evaluation of the diagnostic criteria of each condition and provides crucial insight into the clinical characteristics of very mild forms of syndromic deafness. On the other hand, the clinical condition of Group 2 NSM patients will be evaluated by a multi-disciplinary team in order to provide personalised follow-up and specific preventive strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
4. Usher syndrome: An effective sequencing approach to establish a genetic and clinical diagnosis
- Author
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Lenarduzzi, S., Vozzi, D., Morgan, A., Rubinato, E., DʼEustacchio, A., Osland, T. M., Rossi, C., Graziano, C., Castorina, P., Ambrosetti, U., Morgutti, M., and Girotto, G.
- Published
- 2015
- Full Text
- View/download PDF
5. Obstructive Jaundice in a Three Month-Old Baby
- Author
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Amaddeo, A, Rubinato, E, Schleef, J, Olenik, D, Giglia, D, Marchetti, F, Ventura, Alessandro, Amaddeo, A, Rubinato, E, Schleef, J, Olenik, D, Giglia, D, Marchetti, F, and Ventura, Alessandro
- Subjects
children - Abstract
N/A
- Published
- 2014
6. Hereditary hearing loss: a 96 gene targeted sequencing protocol reveals novel alleles in a series of Italian and Qatari patients
- Author
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Vozzi, D., primary, Morgan, A., additional, Vuckovic, D., additional, D'Eustacchio, A., additional, Abdulhadi, K., additional, Rubinato, E., additional, Badii, R., additional, Gasparini, P., additional, and Girotto, G., additional
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- 2014
- Full Text
- View/download PDF
7. Pendred Syndrome, or Not Pendred Syndrome? That Is the Question
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Giorgia Girotto, Daniele Dell'Orco, Anna Morgan, Paola Tesolin, Elisa Rubinato, Lydie Ammar, Claudio Granata, Eva Orzan, Stefania Lenarduzzi, Sofia Fiorino, Elisabetta Cattaruzzi, Veronica Castro, Tesolin, P., Fiorino, S., Lenarduzzi, S., Rubinato, E., Cattaruzzi, E., Ammar, L., Castro, V., Orzan, E., Granata, C., Dell'Orco, D., Morgan, A., and Girotto, G.
- Subjects
Adult ,Male ,Candidate gene ,Genotype-phenotype correlation ,Adolescent ,Pendred syndrome ,Hearing Loss, Sensorineural ,Myosin Type V ,Biology ,genotype-phenotype correlation ,QH426-470 ,Compound heterozygosity ,Article ,Young Adult ,Exome Sequencing ,medicine ,otorhinolaryngologic diseases ,Genetics ,Humans ,Genetic Predisposition to Disease ,Multiplex ligation-dependent probe amplification ,Whole-Exome Sequencing ,Child ,Genetics (clinical) ,Exome sequencing ,Genetic Association Studies ,Haplotype ,Infant ,medicine.disease ,Major gene ,Whole-exome sequencing ,Haplotypes ,Sulfate Transporters ,Child, Preschool ,Mutation ,Female ,Protein stabilization ,Goiter, Nodular - Abstract
Pendred syndrome (PDS) is the most common form of syndromic Hearing Loss (HL), characterized by sensorineural HL, inner ear malformations, and goiter, with or without hypothyroidism. SLC26A4 is the major gene involved, even though ~50% of the patients carry only one pathogenic mutation. This study aims to define the molecular diagnosis for a cohort of 24 suspected-PDS patients characterized by a deep radiological and audiological evaluation. Whole-Exome Sequencing (WES), the analysis of twelve variants upstream of SLC26A4, constituting the “CEVA haplotype” and Multiplex Ligation Probe Amplification (MLPA) searching for deletions/duplications in SLC26A4 gene have been carried out. In five patients (20.8%) homozygous/compound heterozygous SLC26A4 mutations, or pathogenic mutation in trans with the CEVA haplotype have been identified, while five subjects (20.8%) resulted heterozygous for a single variant. In silico protein modeling supported the pathogenicity of the detected variants, suggesting an effect on the protein stabilization/function. Interestingly, we identified a genotype-phenotype correlation among those patients carrying SLC26A4 mutations, whose audiograms presented a characteristic slope at the medium and high frequencies, providing new insights into PDS. Finally, an interesting homozygous variant in MYO5C has been identified in one patient negative to SLC26A4 gene, suggesting the identification of a new HL candidate gene.
- Published
- 2021
8. Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss
- Author
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Navaneethakrishnan Krishnamoorthy, Elisa Rubinato, Martina La Bianca, Paolo Gasparini, Umberto Ambrosetti, Diego Vozzi, Annamaria Franzè, Dragana Vuckovic, Giorgia Girotto, Mariateresa Di Stazio, Pierangela Castorina, Stefania Cappellani, Anna Morgan, Morgan, A, Vuckovic, D, Krishnamoorthy, N, Rubinato, E, Ambrosetti, U, Castorina, P, Franze', Annamaria, Vozzi, D, La Bianca, M, Cappellani, S, Di Stazio, M, Gasparini, P, Girotto, G, Morgan, Anna, Vuckovic, Dragana, Krishnamoorthy, Navaneethakrishnan, Rubinato, Elisa, Ambrosetti, Umberto, Castorina, Pierangela, Franzè, Annamaria, Vozzi, Diego, La Bianca, Martina, Cappellani, Stefania, Di Stazio, Mariateresa, Gasparini, Paolo, and Girotto, Giorgia
- Subjects
Male ,Candidate gene ,Next-generation Sequencing ,Hearing loss ,Hearing Loss ,SPATC1L ,Population ,Mutation, Missense ,Biology ,Article ,Frameshift mutation ,03 medical and health sciences ,Mice ,Genetics ,medicine ,otorhinolaryngologic diseases ,Missense mutation ,Animals ,Humans ,Allele ,education ,Hearing Lo ,Genetics (clinical) ,Exome sequencing ,Genetic association ,Genetics & Heredity ,0604 Genetics ,0303 health sciences ,education.field_of_study ,Protein Stability ,030305 genetics & heredity ,Middle Aged ,Cytoskeletal Proteins ,HEK293 Cells ,Codon, Nonsense ,Female ,medicine.symptom - Abstract
Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants in SPATC1L: a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstrating Spatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association of SPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role of SPATC1L in hearing function and loss.
- Published
- 2019
9. Which Came First? When Usher Syndrome Type 1 Couples with Neuropsychiatric Disorders.
- Author
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Tesolin P, Santin A, Morgan A, Lenarduzzi S, Rubinato E, Girotto G, and Spedicati B
- Abstract
Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss (HL), retinopathy, and vestibular areflexia, with variable severity. Although a high prevalence of behavioural and mental disorders in USH patients has been reported, few studies on these psychiatric and psychological issues have been conducted. This work describes the case of a 16-year-old boy affected by congenital bilateral sensorineural HL, presenting a suddenly altered behaviour concomitant with a decrease in visual acuity. To establish a molecular diagnosis, Whole-Exome Sequencing analysis was performed, detecting a pathogenetic homozygous variant (c. 5985C>A, p.(Tyr1995*)) within the CDH23 gene. CDH23 is a known USH type 1 causative gene, recently associated with schizophrenia-like symptoms and bipolar disorders. To date, no studies have provided evidence of a direct genotype-phenotype correlation between USH patients carrying CDH23 variants and mental/behavioural issues; however, considering the multiple biological functions of CDH23 , it can be hypothesised that it could have a pleiotropic effect. Overall, this study highlights the relevance of a continuous clinical evaluation of USH patients, to monitor not only the disease progression, but to early detect any psychological or behavioural alterations, thus allowing a rapid implementation of therapeutic strategies aimed at improving their quality of life and well-being.
- Published
- 2023
- Full Text
- View/download PDF
10. Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment.
- Author
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Jonard L, Brotto D, Moreno-Pelayo MA, Del Castillo I, Kremer H, Pennings R, Caria H, Fialho G, Boudewyns A, Van Camp G, Ołdak M, Oziębło D, Deggouj N, De Siati RD, Gasparini P, Girotto G, Verstreken M, Dossena S, Roesch S, Battelino S, Trebušak Podkrajšek K, Warnecke A, Lenarz T, Lesinski-Schiedat A, Mondain M, Roux AF, Denoyelle F, Loundon N, Serey Gaut M, Trevisi P, Rubinato E, Martini A, and Marlin S
- Abstract
The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].
- Published
- 2023
- Full Text
- View/download PDF
11. The Enigmatic Genetic Landscape of Hereditary Hearing Loss: A Multistep Diagnostic Strategy in the Italian Population.
- Author
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Spedicati B, Santin A, Nardone GG, Rubinato E, Lenarduzzi S, Graziano C, Garavelli L, Miccoli S, Bigoni S, Morgan A, and Girotto G
- Abstract
Hearing loss is the most frequent sensorineural disorder, affecting approximately 1:1000 newborns. Hereditary forms (HHL) represent 50-60% of cases, highlighting the relevance of genetic testing in deaf patients. HHL is classified as non-syndromic (NSHL-70% of cases) or syndromic (SHL-30% of cases). In this study, a multistep and integrative approach aimed at identifying the molecular cause of HHL in 102 patients, whose GJB2 analysis already showed a negative result, is described. In NSHL patients, multiplex ligation probe amplification and long-range PCR analyses of the STRC gene solved 13 cases, while whole exome sequencing (WES) identified the genetic diagnosis in 26 additional ones, with a total detection rate of 47.6%. Concerning SHL, WES detected the molecular cause in 55% of cases. Peculiar findings are represented by the identification of four subjects displaying a dual molecular diagnosis and eight affected by non-syndromic mimics, five of them presenting Usher syndrome type 2. Overall, this study provides a detailed characterisation of the genetic causes of HHL in the Italian population. Furthermore, we highlighted the frequency of Usher syndrome type 2 carriers in the Italian population to pave the way for a more effective implementation of diagnostic and follow-up strategies for this disease.
- Published
- 2023
- Full Text
- View/download PDF
12. New insights on Noonan syndrome's clinical phenotype: a single center retrospective study.
- Author
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Baldo F, Fachin A, Da Re B, Rubinato E, Bobbo M, and Barbi E
- Subjects
- Child, Humans, Genetic Testing, Intracellular Signaling Peptides and Proteins genetics, Mutation, Phenotype, Retrospective Studies, SOS1 Protein genetics, Proto-Oncogene Proteins p21(ras) genetics, Noonan Syndrome diagnosis, Noonan Syndrome genetics
- Abstract
Background: Noonan syndrome (NS) is a clinically and genetically heterogeneous disorder. Since its clinical phenotype is often mild and difficult to differentiate from other syndromes, its diagnosis can be challenging and its prevalence in the pediatric population is most certainly underestimated. The difficulty in identifying Noonan syndrome is also increased by the fact that genetic tests are currently not able to detect an underlying mutation in around 10% of the cases., Methods: This is a retrospective, observational study conducted at the Institute for Maternal and Child "Burlo Garofolo" in Trieste, Italy. We recruited all the patients with clinical and/or genetic diagnosis of NS who were evaluated at the Department of Pediatrics between October 2015 and October 2020. Statistical analyses were performed with IBM SPSS Statistics software. The association between discrete variables has been evaluated through chi-squared test, indicating statistically significant p with Pearson test or Fischer test for variables less than 5., Results: We recruited a total of 35 patients affected by Noonan syndrome. In 24 patients (75%) we identified an underlying genetic substrate: 17 patients had a mutation on PTPN11 (61%), 2 in SOS1, KRAS and SHOC2 (7% each) and only 1 in RAF1 (4%). 25% of the subjects did not receive a genetic confirm. As for the phenotype of the syndrome, our study identified the presence of some clinical features which were previously unrelated or poorly related to NS. For example, renal and central nervous system abnormalities were found at a higher rate compared to the current literature. On the contrary, some features that are considered very suggestive of NS (such as lymphatic abnormalities and the classical facial features) were not frequently found in our population., Conclusions: In our analysis, we focused on the main phenotypic features of NS, identifying various clinical manifestation that were not associated with this genetic condition before. This could be helpful in raising the knowledge of NS's clinical spectrum, facilitating its diagnosis., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
13. Challenging Occam's Razor: Dual Molecular Diagnoses Explain Entangled Clinical Pictures.
- Author
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Spedicati B, Morgan A, Pianigiani G, Musante L, Rubinato E, Santin A, Nardone GG, Faletra F, and Girotto G
- Subjects
- Phenotype, Family, Genomics, Multifactorial Inheritance
- Abstract
Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report the identification of double genetic disorders in a series of patients with complex clinical features. In the last 24 months, 342 syndromic patients have been recruited and clinically characterised. Whole Exome Sequencing analysis has been performed on the proband and on both parents and identified seven patients affected by a dual molecular diagnosis. Upon a detailed evaluation of both their clinical and molecular features, subjects are able to be divided into two groups: (A) five patients who present distinct phenotypes, due to each of the two different underlying genetic diseases; (B) two patients with overlapping clinical features that may be underpinned by both the identified genetic variations. Notably, only in one case a multilocus genomic variation was already suspected during the clinical evaluation. Overall, our findings highlight how dual molecular diagnoses represent a challenging model of complex inheritance that should always be considered whenever a patient shows atypical clinical features. Indeed, an accurate genetic characterisation is of the utmost importance to provide patients with a personalised and safe clinical management.
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- 2022
- Full Text
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14. Long QT syndrome and left ventricular non-compaction in a family with KCNH2 mutation: A case report.
- Author
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Caiffa T, Tessitore A, Leoni L, Reffo E, Chicco D, D'Agata Mottolese B, Rubinato E, Girotto G, Lenarduzzi S, Barbi E, Bobbo M, and Di Salvo G
- Abstract
Background: Left ventricular non-compaction (LVNC) is an abnormality of the myocardium, characterized by prominent left ventricular trabeculae and deep inter-trabecular recesses. Long QT syndrome (LQTS) is a cardiac ion channelopathy presenting with a prolonged QT interval on resting electrocardiogram and is associated with increased susceptibility to sudden death. The association between LVNC and LQTS is uncommon., Case Presentation: We report an Italian family with a novel pathogenic KCNH2 variant who presented with clinical features of LVNC and LQTS. The proband came to our attention after two syncopal episodes without prodromal symptoms. His ECG showed QTc prolongation and deep T wave inversion in anterior leads, and the echocardiogram fulfilled LVNC criteria. After that, also his sister was found to have LQTS and LVNC, while his father only presented LQTS., Conclusions: Physicians should be aware of the possible association between LVNC and LQTS. Even if this association is rare, patients with LVNC should be investigated for LQTS to prevent possible severe or even life-threatening arrhythmic episodes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Caiffa, Tessitore, Leoni, Reffo, Chicco, D'Agata Mottolese, Rubinato, Girotto, Lenarduzzi, Barbi, Bobbo and Di Salvo.)
- Published
- 2022
- Full Text
- View/download PDF
15. Pendred Syndrome, or Not Pendred Syndrome? That Is the Question.
- Author
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Tesolin P, Fiorino S, Lenarduzzi S, Rubinato E, Cattaruzzi E, Ammar L, Castro V, Orzan E, Granata C, Dell'Orco D, Morgan A, and Girotto G
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Predisposition to Disease, Goiter, Nodular epidemiology, Goiter, Nodular pathology, Haplotypes genetics, Hearing Loss, Sensorineural epidemiology, Hearing Loss, Sensorineural pathology, Humans, Infant, Male, Mutation, Exome Sequencing, Young Adult, Goiter, Nodular genetics, Hearing Loss, Sensorineural genetics, Myosin Type V genetics, Sulfate Transporters genetics
- Abstract
Pendred syndrome (PDS) is the most common form of syndromic Hearing Loss (HL), characterized by sensorineural HL, inner ear malformations, and goiter, with or without hypothyroidism. SLC26A4 is the major gene involved, even though ~50% of the patients carry only one pathogenic mutation. This study aims to define the molecular diagnosis for a cohort of 24 suspected-PDS patients characterized by a deep radiological and audiological evaluation. Whole-Exome Sequencing (WES), the analysis of twelve variants upstream of SLC26A4 , constituting the "CEVA haplotype" and Multiplex Ligation Probe Amplification (MLPA) searching for deletions/duplications in SLC26A4 gene have been carried out. In five patients (20.8%) homozygous/compound heterozygous SLC26A4 mutations, or pathogenic mutation in trans with the CEVA haplotype have been identified, while five subjects (20.8%) resulted heterozygous for a single variant. In silico protein modeling supported the pathogenicity of the detected variants, suggesting an effect on the protein stabilization/function. Interestingly, we identified a genotype-phenotype correlation among those patients carrying SLC26A4 mutations, whose audiograms presented a characteristic slope at the medium and high frequencies, providing new insights into PDS. Finally, an interesting homozygous variant in MYO5C has been identified in one patient negative to SLC26A4 gene, suggesting the identification of a new HL candidate gene.
- Published
- 2021
- Full Text
- View/download PDF
16. PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review.
- Author
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Mercati O, Abi Warde MT, Lina-Granade G, Rio M, Heide S, de Lonlay P, Ceballos-Picot I, Robert MP, Couloigner V, Beltrand J, Boddaert N, Rodriguez D, Rubinato E, Lapierre JM, Merlette C, Sanquer S, Rötig A, Prokisch H, Lyonnet S, Loundon N, Kaplan J, Bonnefont JP, Munnich A, Besmond C, Jonard L, and Marlin S
- Subjects
- Ataxia pathology, Child, Deaf-Blind Disorders pathology, Female, Genetic Diseases, X-Linked pathology, Humans, Infant, Intellectual Disability pathology, Male, Pedigree, Ataxia genetics, Deaf-Blind Disorders genetics, Genetic Diseases, X-Linked genetics, Intellectual Disability genetics, Loss of Function Mutation, Phenotype, Ribose-Phosphate Pyrophosphokinase genetics
- Abstract
We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this rare condition, both in females and in males. Moreover, our observation of a new family in which hemizygous males display hearing loss without any neurological or ophthalmological symptoms prompts us to suggest analysing PRPS1 in cases of isolated hearing loss. Eventually, PRPS1 variants should be considered as a differential diagnosis of mitochondrial disorders., (Copyright © 2020. Published by Elsevier Masson SAS.)
- Published
- 2020
- Full Text
- View/download PDF
17. MED12 missense mutation in a three-generation family. Clinical characterization of MED12-related disorders and literature review.
- Author
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Rubinato E, Rondeau S, Giuliano F, Kossorotoff M, Parodi M, Gherbi S, Steffan J, Jonard L, and Marlin S
- Subjects
- Abnormalities, Multiple physiopathology, Adolescent, Agenesis of Corpus Callosum physiopathology, Anus, Imperforate physiopathology, Blepharophimosis physiopathology, Blepharoptosis physiopathology, Child, Constipation physiopathology, Craniofacial Abnormalities physiopathology, Genes, X-Linked, Hearing Loss genetics, Hearing Loss physiopathology, Heart Defects, Congenital physiopathology, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability physiopathology, Male, Marfan Syndrome physiopathology, Mental Retardation, X-Linked physiopathology, Middle Aged, Muscle Hypotonia genetics, Muscle Hypotonia physiopathology, Mutation, Missense, Pedigree, Abnormalities, Multiple genetics, Agenesis of Corpus Callosum genetics, Anus, Imperforate genetics, Blepharophimosis genetics, Blepharoptosis genetics, Constipation genetics, Craniofacial Abnormalities genetics, Heart Defects, Congenital genetics, Intellectual Disability genetics, Marfan Syndrome genetics, Mediator Complex genetics, Mental Retardation, X-Linked genetics, Muscle Hypotonia congenital
- Abstract
Mutations in MED12 gene have been described in association with syndromic and non-syndromic X-linked intellectual disability (XLID). Up to date at least three distinct XLID syndromes have been described: FG syndrome, Lujan-Fryns syndrome (LS) and Ohdo syndrome (OSMKB). In the last years, thanks to the massive use of next generation sequencing techniques (NGS) it has been possible to discover at least 16 others MED12 mutations and to expand the phenotype of MED12-related disorders. Here we report three subjects from a large non-consanguineous family presenting with a mild to severe ID, important speech delay, behavior problems, dysmorphic facial features and hearing loss. NGS allows us to detect the MED12 missense variant c.3883C > T (p.(Arg1295Cys)) carried by the three patients. This variant has been reported in 2016 by Hu et al. in one family from a big cohort of XLID families. This clinical report contributes to expanding the phenotype associated with MED12-mutations., (Copyright © 2019. Published by Elsevier Masson SAS.)
- Published
- 2020
- Full Text
- View/download PDF
18. TBL1Y: a new gene involved in syndromic hearing loss.
- Author
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Di Stazio M, Collesi C, Vozzi D, Liu W, Myers M, Morgan A, D Adamo PA, Girotto G, Rubinato E, Giacca M, and Gasparini P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cochlea metabolism, Female, Genetic Diseases, Y-Linked pathology, Hearing Loss pathology, Humans, Male, Middle Aged, Mutation, Missense, Pedigree, Prostate metabolism, Prostatic Hyperplasia pathology, Protein Stability, Syndrome, Transducin metabolism, Genetic Diseases, Y-Linked genetics, Hearing Loss genetics, Prostatic Hyperplasia genetics, Transducin genetics
- Abstract
Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss. Here, we demonstrate that it has a restricted expression in adult human cochlea and prostate and the variant identified induces a lower protein stability caused by misfolded mutated protein that impairs its cellular function. These findings indicate that TBL1Y could be considered a novel candidate for HHL.
- Published
- 2019
- Full Text
- View/download PDF
19. Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss.
- Author
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Morgan A, Vuckovic D, Krishnamoorthy N, Rubinato E, Ambrosetti U, Castorina P, Franzè A, Vozzi D, La Bianca M, Cappellani S, Di Stazio M, Gasparini P, and Girotto G
- Subjects
- Animals, Codon, Nonsense, Cytoskeletal Proteins chemistry, Cytoskeletal Proteins metabolism, Female, HEK293 Cells, Humans, Male, Mice, Middle Aged, Mutation, Missense, Protein Stability, Cytoskeletal Proteins genetics, Hearing Loss genetics
- Abstract
Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants in SPATC1L: a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstrating Spatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association of SPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role of SPATC1L in hearing function and loss.
- Published
- 2019
- Full Text
- View/download PDF
20. PSIP1/LEDGF: a new gene likely involved in sensorineural progressive hearing loss.
- Author
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Girotto G, Scheffer DI, Morgan A, Vozzi D, Rubinato E, Di Stazio M, Muzzi E, Pensiero S, Giersch AB, Corey DP, and Gasparini P
- Subjects
- Adaptor Proteins, Signal Transducing chemistry, Adaptor Proteins, Signal Transducing metabolism, Adolescent, Adult, Amino Acid Sequence, Animals, Base Sequence, DNA Mutational Analysis, Ear, Inner, Exome genetics, Family, Female, Frameshift Mutation genetics, Gene Expression Regulation, Humans, Male, Mice, Molecular Sequence Data, Mutation genetics, Pedigree, RNA Stability genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Analysis, RNA, Transcription Factors chemistry, Transcription Factors metabolism, Young Adult, Adaptor Proteins, Signal Transducing genetics, Genetic Predisposition to Disease, Hearing Loss, Sensorineural genetics, Transcription Factors genetics
- Abstract
Hereditary Hearing Loss (HHL) is an extremely heterogeneous disorder. Approximately 30 out of 80 known HHL genes are associated with autosomal dominant forms. Here, we identified PSIP1/LEDGF (isoform p75) as a novel strong candidate gene involved in dominant HHL. Using exome sequencing we found a frameshift deletion (c.1554_1555del leading to p.E518Dfs*2) in an Italian pedigree affected by sensorineural mild-to-moderate HHL but also showing a variable eye phenotype (i.e. uveitis, optic neuropathy). This deletion led to a premature stop codon (p.T519X) with truncation of the last 12 amino acids. PSIP1 was recently described as a transcriptional co-activator regulated by miR-135b in vestibular hair cells of the mouse inner ear as well as a possible protector against photoreceptor degeneration. Here, we demonstrate that it is ubiquitously expressed in the mouse inner ear. The PSIP1 mutation is associated with a peculiar audiometric slope toward the high frequencies. These findings indicate that PSIP1 likely plays an important role in HHL.
- Published
- 2015
- Full Text
- View/download PDF
21. Obstructive jaundice in a 3-month-old baby.
- Author
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Amaddeo A, Rubinato E, Schleef J, Olenik D, Giglia D, Marchetti F, and Ventura A
- Subjects
- Common Bile Duct diagnostic imaging, Constriction, Pathologic congenital, Constriction, Pathologic diagnostic imaging, Female, Humans, Infant, Radiography, Common Bile Duct abnormalities, Jaundice, Obstructive etiology
- Published
- 2014
- Full Text
- View/download PDF
22. A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta.
- Author
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Rubinato E, Morgan A, D'Eustacchio A, Pecile V, Gortani G, Gasparini P, and Faletra F
- Subjects
- Child, Chromosomes, Human, Pair 19, DNA Mutational Analysis, Exons, Female, Homozygote, Humans, Osteogenesis Imperfecta diagnostic imaging, Radiography, Genes, Recessive, Ion Channels genetics, Osteogenesis Imperfecta genetics, Sequence Deletion
- Abstract
Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
23. A girl with photosensitivity and hepatic steatosis.
- Author
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Pavan M, Gortani G, Rubinato E, Faletra F, Pastore S, and Ventura A
- Subjects
- Child, Diagnosis, Differential, Fatty Liver diagnosis, Female, Humans, Photosensitivity Disorders diagnosis, Protoporphyria, Erythropoietic genetics, Fatty Liver complications, Photosensitivity Disorders complications, Protoporphyria, Erythropoietic diagnosis
- Published
- 2014
- Full Text
- View/download PDF
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