Background Turner’s syndrome is associated with either monosomy or a wide spectrum of structural rearrangements of chromosome X. Despite the interest in studying (somatic) chromosomal mosaicism, Turner’s syndrome mosaicism (TSM) remains to be fully described. This is especially true for the analysis of TSM in clinical cohorts (e.g. cohorts of individuals with neurodevelopmental disorders). Here, we present the results of studying TSM in a large cohort of girls with neurodevelopmental disorders and a hypothesis highlighting the diagnostic and prognostic value. Results Turner’s syndrome-associated karyotypes were revealed in 111 (2.8%) of 4021 girls. Regular Turner’s syndrome-associated karyotypes were detected in 35 girls (0.9%). TSM was uncovered in 76 girls (1.9%). TSM manifested as mosaic aneuploidy (45,X/46,XX; 45,X/47,XXX/46,XX; 45,X/47,XXX) affected 47 girls (1.2%). Supernumerary marker chromosomes derived from chromosome X have been identified in 11 girls with TSM (0.3%). Isochromosomes iX(q) was found in 12 cases (0.3%); one case was non-mosaic. TSM associated with ring chromosomes was revealed in 5 girls (0.1%). Conclusion The present cohort study provides data on the involvement of TSM in neurodevelopmental disorders among females. Thus, TSM may be an element of pathogenic cascades in brain diseases (i.e. neurodegenerative and psychiatric disorders). Our data allowed us to propose a hypothesis concerning ontogenetic variability of TSM levels. Accordingly, it appears that molecular cytogenetic monitoring of TSM, which is a likely risk factor/biomarker for adult-onset multifactorial diseases, is required.

Background Klinefelter syndrome is a common chromosomal (aneuploidy) disorder associated with an extra X chromosome in males. Regardless of numerous studies dedicated to somatic gonosomal mosaicism, Klinefelter syndrome mosaicism (KSM) has not been systematically addressed in clinical cohorts. Here, we report on the evaluation of KSM in a large cohort of boys with neurodevelopmental disorders. Furthermore, these data have been used for an extension of the hypothesis, which we have recently proposed in a report on Turner’s syndrome mosaicism in girls with neurodevelopmental disorders. Results Klinefelter syndrome-associated karyotypes were revealed in 49 (1.1%) of 4535 boys. Twenty one boys (0.5%) were non-mosaic 47,XXY individuals. KSM was found in 28 cases (0.6%) and manifested as mosaic aneuploidy (50,XXXXXY; 49,XXXXY; 48,XXXY; 48,XXYY; 47,XXY; and 45,X were detected in addition to 47,XXY/46,XY) and mosaic supernumerary marker chromosomes derived from chromosome X (ring chromosomes X and rearranged chromosomes X). It is noteworthy that KSM was concomitant with Rett-syndrome-like phenotypes caused by MECP2 mutations in 5 boys (0.1%). Conclusion Our study provides data on the occurrence of KSM in neurodevelopmental disorders among males. Accordingly, it is proposed that KSM may be a possible element of pathogenic cascades in psychiatric and neurodegenerative diseases. These observations allowed us to extend the hypothesis proposed in our previous report on the contribution of somatic gonosomal mosaicism (Turner’s syndrome mosaicism) to the etiology of neurodevelopmental disorders. Thus, it seems to be important to monitor KSM (a possible risk factor or a biomarker for adult-onset multifactorial brain diseases) and analysis of neuromarkers for aging in individuals with Klinefelter syndrome. Cases of two or more supernumerary chromosomes X were all associated with KSM. Finally, Rett syndrome-like phenotypes associated with KSM appear to be more common in males with neurodevelopmental disorders than previously recognized.

Despite the achievements of human genomics, comprehensive genome analysis, including acquiring the knowledge about intercellular and interindividual variations at (sub)chromosomal/ cytogenomic level, remains a difficult task. This basically results from a lack of heuristic algorithms for uncovering (cyto)genomic and/or somatic genome variations and the functional outcomes. However, current developments in molecular cytogenetics and “cytopostgenomics” may offer a solution of the problem. The aim of the study: To present a heuristic algorithm for molecular cytogenetic and cytopostgenomic analysis of the human genome to uncover mechanisms of genetic (brain/neurodevelopmental) diseases. Materials and methods: Data on cytogenetic and (cyto)genomic variations (chromosome abnormalities, chromosome/genome instability, copy number variation (CNV) etc.) addressed by original molecular cytogenetic techniques and processed by original bioinformatic (cytopostgenomic) methods were used to develop the algorithm. Karyotyping was performed in 8556 individuals. FISH analysis was applied when required (cases of somatic mosaicism/ chromosome instability). Molecular karyotyping by SNP-array was performed in 600 (~7%) cases. Results: Using our long-term experience of studying chromosomal and genomic variations/instability in neurodevelopmental disorders as well as original developments in (cyto) genomic data processing, we managed to present a heuristic algorithm for molecular cytogenetic and cytopostgenomic analysis of the human genome to uncover mechanisms for brain diseases. Estimated efficiency of the algorithm was established to achieve 84%. Analyzing the dynamics of applying cytogenetic and cytogenomic techniques throughout ~35 years of our diagnostic research we found that the diagnostic efficiency had been increasing from ~7% (exclusive diagnosis by karyotyping) to more than 80% (molecular cytogenetic and cytopostgenomic analysis). Conclusion: Here, we propose a heuristic algorithm for molecular cytogenetic and cytopostgenomic analysis of the human genome to uncover mechanisms for genetic diseases. The efficiency and ability to uncover mechanisms of chromosome instability allows us to conclude that the algorithm may be highly competitive for basic and diagnostic genomic/cyto(post)genomic research.