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- Usher syndrome and Nebulin‐associated myopathy in a single patient due to variants in MYO7A and NEBPublication . Maia, N; Soares, Ana Rita; Fortuna, Ana; Marques, Isabel; Gonçalves, Ana; Santos, Rosário; Pires, Manuel; De Brouwer, Arjan; Jorge, PaulaIn a patient with Usher syndrome and atypical muscle complaints, we have identified two separate variants in MYO7A andNEB genes by exome sequencing. The homozygous variants in these two recessive genes could explain the full phenotype of our patient.
- 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.
- Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?Publication . Maia, N; Nabais Sá, Maria João; Oliveira, Cláudia; Santos, Flávia; Soares, Celia A; Prior, Catarina; Tkachenko, Nataliya; Santos, Rosário; de Brouwer, Arjan P. M.; Jacome, Ariana; Porto, Beatriz; Jorge, PaulaWe describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient's chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype-phenotype correlations and motivating the biochemical study of the underlying mechanisms.
- Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele CombinationsPublication . Rodrigues, Bárbara; Vale-Fernandes, Emídio; Maia, N; Santos, Flávia; Marques, Isabel; Santos, Rosário; Nogueira, António J. A.; Jorge, PaulaThe polymorphic trinucleotide repetitive region in the FMR1 gene 5'UTR contains AGG interspersions, particularly in normal-sized alleles (CGG < 45). In this range repetitive stretches are typically interrupted once or twice, although alleles without or with three or more AGG interspersions can also be observed. AGG interspersions together with the total length of the repetitive region confer stability and hinder expansion to pathogenic ranges: either premutation (55 < CGG < 200) or full mutation (CGG > 200). The AGG interspersions have long been identified as one of the most important features of FMR1 repeat stability, being particularly important to determine expansion risk estimates in female premutation carriers. We sought to compute the combined AGG interspersion numbers and patterns, aiming to define FMR1 repetitive tract complexity combinations. A mathematical model, the first to compute this cumulative effect, was developed and validated using data from 131 young and healthy females. Plotting of their allelic complexity enabled the identification of two statistically distinct groups - equivalent and dissimilar allelic combinations. The outcome, a numerical parameter designated allelic score, depicts the repeat substructure of each allele, measuring the allelic complexity of the FMR1 gene including the AGGs burden, thus allowing new behavioral scrutiny of normal-sized alleles in females.
- Advances in fragile-x testingPublication . Maia, N.; Marques, Isabel; Jorge, P.; Santos, Rosário