Browsing by Author "Soares, Gabriela"
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- Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental DisorderPublication . Bain, Jennifer M.; Thornburg, Olivia; Pan, Cheryl; Rome-Martin, Donnielle; Boyle, Lia; Fan, Xiao; Devinsky, Orrin; Frye, Richard; Hamp, Silke; Keator, Cynthia G.; LaMarca, Nicole M.; Maddocks, Alexis B.R.; Madruga-Garrido, Marcos; Niederhoffer, Karen Y.; Novara, Francesca; Peron, Angela; Poole-Di Salvo, Elizabeth; Salazar, Rachel; Skinner, Steven A.; Soares, Gabriela; Goldman, Sylvie; Chung, Wendy K.Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.
- Genomic imbalances defining novel intellectual disability associated lociPublication . Lopes, Fátima; Torres, Fátima; Soares, Gabriela; Barbosa, Mafalda; Silva, João; Duque, Frederico; Rocha, Miguel; Sá, Joaquim; Oliveira, Guiomar; Sá, Maria João; Temudo, Teresa; Sousa, Susana; Marques, Carla; Lopes, Sofia; Gomes, Catarina; Barros, Gisela; Jorge, Arminda; Rocha, Felisbela; Martins, Cecília; Mesquita, Sandra; Loureiro, Susana; Cardoso, Elisa Maria; Cálix, Maria José; Dias, Andreia; Martins, Cristina; Mota, Céu R; Antunes, Diana; Dupont, Juliette; Figueiredo, Sara; Figueiroa, Sónia; Gama-de-Sousa, Susana; Cruz, Sara; Sampaio, Adriana; Eijk, Paul; Weiss, Marjan M; Ylstra, Bauke; Rendeiro, Paula; Tavares, Purificação; Reis-Lima, Margarida; Pinto-Basto, Jorge; Fortuna, Ana Maria; Maciel, PatríciaBackground: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). Results: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. Conclusions: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.
- Two Compound Heterozygous Variants in SNX14 Cause Stereotypies and Dystonia in Autosomal Recessive Spinocerebellar Ataxia 20Publication . Maia, N; Soares, Gabriela; Silva, Cecília; Marques, Isabel; Rodrigues, Bárbara; Santos, Rosário; Melo-Pires, Manuel; de Brouwer, Arjan PM; Temudo, Teresa; Jorge, PaulaAutosomal Recessive Spinocerebellar Ataxia 20, SCAR20, is a rare condition characterized by intellectual disability, lack of speech, ataxia, coarse facies and macrocephaly, caused by SNX14 variants. While all cases described are due to homozygous variants that generally result in loss of protein, so far there are no other cases of reported compound heterozygous variants. Here we describe the first non-consanguineous SCAR20 family, the second Portuguese, with two siblings presenting similar clinical features caused by compound heterozygous SNX14 variants: NM_001350532.1:c.1195C>T, p.(Arg399*) combined with a novel complex genomic rearrangement. Quantitative PCR (Q-PCR), long-range PCR and sequencing was used to elucidate the region and mechanisms involved in the latter: two deletions, an inversion and an AG insertion: NM_001350532.1:c.[612+3028_698-2759del;698-2758_698-516inv;698-515_1171+1366delinsAG]. In silico analyses of these variants are in agreement with causality, enabling a genotype-phenotype correlation in both patients. Clinical phenotype includes dystonia and stereotypies never associated with SCAR20. Overall, this study allowed to extend the knowledge of the phenotypic and mutational spectrum of SCAR20, and to validate the role of Sorting nexin-14 in a well-defined neurodevelopmental syndrome, which can lead to cognitive impairment. We also highlight the value of an accurate clinical evaluation and deep phenotyping to disclose the molecular defect underlying highly heterogeneous condition such as intellectual disability.