A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation.

Yin and Yang 1 gene (YY1; MIM#600,013) is recognized as a dual transcriptional activating and repressing factor, RNA-binding protein, and 3D chromatin regulator, with multi roles in neurodevelopmental and maintenance pathways. YY1 haploinsufficiency caused either by heterozygous sequence variants or deletions involving the whole gene has been recently associated with Gabriele-de Vries syndrome (GADEVS), a rare congenital autosomal dominant condition, leading to intellectual disability (ID) and multiple physical/behavioural abnormalities. Herein, we describe clinical and molecular findings from a Brazilian female harbouring a de novo missense pathogenic variant in YY1 gene (NM_003403.5:c.1106A > G; p.Asn369Ser) found by whole exome sequencing with potential implications for protein structure and function. Undescribed or uncommon clinical features in this patient included non-febrile seizures, severe scoliosis, hearing impairment, and chorioretinitis. Further bioinformatics analyses using YY1-other protein interaction networks reinforced the involvement of YY1 interactors in such phenotypes, in exception of chorioretinitis. Moreover, X-chromosome inactivation (XCI) skewing was evidenced in the patient and attributed to the haploinsufficiency of YY1, which direct and indirectly interacts with numerous XCI key regulators. Besides expanding the mutational and phenotype spectrum of GADEVS, our results highlight the role of YY1 as an essential autosomal regulator of XCI epigenetic process.

Molecular and clinical insights into complex genomic rearrangements related to MECP2 duplication syndrome.

MECP2 duplication syndrome (MDS) is caused by copy number variation (CNV) spanning the MECP2 gene at Xq28 and is a major cause of intellectual disability (ID) in males. Herein, we describe two unrelated males harboring non-recurrent complex Xq28 rearrangements associated with MDS. Copy number gains were initially detected by quantitative real-time polymerase chain reaction and further delineated by high-resolution array comparative genomic hybridization, familial segregation, expression analysis and X-chromosome inactivation (XCI) evaluation in a carrier mother. SNVs within the rearrangements and/or fluorescent in situ hybridization (FISH) were used to assess the parental origin of the rearrangements. Patient 1 exhibited an intrachromosomal rearrangement, whose structure is consistent with a triplicated segment presumably embedded in an inverted orientation between two duplicated sequences (DUP-TRP/INV-DUP). The rearrangement was inherited from the carrier mother, who exhibits extreme XCI skewing and subtle psychiatric symptoms. Patient 2 presented a de novo (X;Y) unbalanced translocation resulting in duplication of Xq28 and deletion of Yp, originated in the paternal gametogenesis. Neurodevelopmental trajectory and non-neurological symptoms were consistent with previous reports, with the exception of cerebellar vermis hypoplasia in patient 2. Although both patients share the core MDS phenotype, patient 1 showed MECP2 transcript levels in blood similar to controls. Understanding the molecular mechanisms related to MDS is essential for designing targeted therapeutic strategies.

Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil.

About 30-70% of familial Alzheimer's disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified. In silico tools were used to predict the functional impact of the variants, revealing no changes in protein functionality by exonic variants. Otherwise, all variants were predicted to alter splicing signals. Prediction results, together with previous reports, suggest a correlation between rs17125721 and AD. So, a subsequent case-control study to evaluate the role of rs1712572 on AD risk was performed in an additional sample of 120 AD sporadic cases and in 149 elderly healthy controls by TaqMan Genotyping Assay. Our data indicates a risk association for rs17125721 in familial AD cases (OR=6.0; IC95%=1.06-33.79; p=0.042). In addition, we tested the multiplicative interaction between allele ε4 of the apolipoprotein E (APOE) and rs17125721 and no statistical association was found. Taken together, our findings provide new insight about the genetic relevance of low frequency PSEN1 variants for familial AD development.

rs3851179 Polymorphism at 5' to the PICALM Gene is Associated with Alzheimer and Parkinson Diseases in Brazilian Population.

Alzheimer's (AD) and Parkinson's diseases (PD) share clinical and pathological features, suggesting that they could have common pathogenic mechanisms, as well as overlapping genetic modifiers. Here, we performed a case-control study in a Brazilian population to clarify whether the risk of AD and PD might be influenced by shared polymorphisms at PICALM (rs3851179), CR1 (rs6656401) and CLU (rs11136000) genes, which were previously identified as AD risk factors by genome-wide association studies. For this purpose, 174 late-onset AD patients, 166 PD patients and 176 matched controls were genotyped using TaqMan® assays. The results revealed that there were significant differences in genotype and allele frequencies for the SNP PICALM rs3851179 between AD/PD cases and controls, but none for CR1 rs6656401 and CLU rs11136000 intronic polymorphisms. After stratification by APOE ε4 status, the protective effect of the PICALM rs3851179 A allele in AD cases remains evident only in APOE ε4 (-) carriers, suggesting that the APOE ε4 risky allele weakens its protective effect in the APOE ε4 (+) subgroup. More genetic studies using large-sized and well-defined matched samples of AD and PD patients from mixed populations as well as functional correlation analysis are urgently needed to clarify the role of rs3851179 in the AD/PD risk. An understanding of the contribution of rs3851179 to the development of AD and PD could provide new targets for the development of novel therapies.