Genetic factors underlying insomnia and ovarian insufficiency.

Premature ovarian insufficiency (POI) is characterized by a loss of regular hormone production and egg release in women below the age of 40 years, which often leads to infertility, vaginal dryness and dysfunctional sleep. Acknowledging the common co-occurrence of insomnia and POI, we tested the overlap between POI and insomnia-associated genes, which were implicated in previous large-scale populational genetics efforts. Among the 27 overlapping genes, three pathways were found as enriched: DNA replication, homologous recombination and Fanconi anemia. We then describe biological mechanisms, which link these pathways to a dysfunctional regulation and response to oxidative stress. We propose that oxidative stress may correspond to one of the convergent cellular processes between ovarian malfunction and insomnia pathogenic etiology. This overlap might also be driven by cortisol release associated with dysregulated DNA repair mechanisms. Benefiting from the enormous advances in populational genetics studies, this study provides a novel outlook on the relationship between insomnia and POI. The shared genetic factors and critical biological nodes between these two comorbidities may lead to identification of putative pharmacological and therapeutical targets, which can leverage novel approaches to treat or alleviate their symptoms.

Phenotypic heterogeneity in 22q11.2 deletion syndrome: Copy Number Variants as genetic modifiers for congenital heart disease in a Brazilian cohort.

The clinical heterogeneity in 22q11.2 deletion syndrome (22q11.2DS) underlies complex genetic mechanisms including variants in other regions of the genome, known as genetic modifiers. Congenital heart disease (CHD) is one of the most relevant phenotypes in the syndrome and copy number variants (CNVs) outside the 22q11.2 region could play a role in its variable expressivity. Since those described loci account for a small proportion of the variability, the CNV analysis in new cohorts from different ancestry-based populations constitutes a valuable resource to identify a wider range of modifiers. We performed SNP-array in 117 Brazilian patients with 22q11.2DS, with and without CHD, and leveraged genome-wide CNV analysis. After quality control, we selected 50 CNVs in 38 patients for downstream analysis. CNVs' genetic content and implicated biological pathways were compared between patients with and without CHD. CNV-affected genes in patients with CHD were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype's expressivity. Cardiac-related genes were identified in both groups of patients suggesting that increasing risk and protective mechanisms could be involved. These genes and enriched pathways could indicate new modifiers to the cardiac phenotype in 22q11.2DS patients.

Different conformation of two supernumerary 18p isochromosomes, one with a concomitant partial 18q trisomy.

The presence of a supernumerary 18p isochromosome is a rare chromosomal abnormality that results in 18p tetrasomy. This is a report on the clinical, cytogenetic and molecular findings of 2 non-related patients with a supernumerary 18p isochromosome. Both patients present some features of the 18p tetrasomy syndrome (strabismus, low-set ears, long and narrow fingers and toes), but additional characteristics were also observed. Cytogenetic analysis, FISH, MLPA and SNP array techniques showed that one of the isochromosomes is symmetric and monocentric, while the other is asymmetric and dicentric, yet resulting in a similar tetrasomy of the 18pter-18p10 region, followed by a partial 18q11.2 trisomy, an unprecedented finding in the literature.