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Outcomes of ROHs (runs of homozygosity)/LCSHs (long contiguous stretches of homozygosity) spanning the imprinted loci of chromosomes 7, 11 and 15 among children with neurodevelopmental disorders

Background: Runs of homozygosity or long contiguous stretches of homozygosity (ROHs/LCSHs) are common in the human genome. ROHs/LCSHs spanning the imprinted loci have been previously associated with neurodevelopmental disorders. However, the outcomes of these epigenomic variations remain enigmatic. Accordingly, there is a need to evaluate the ROHs/LCSHs outcomes covering the imprinted loci. The aim of the study: To describe the outcomes of ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 among children with neurodevelopmental disorders. Materials and methods: Using molecular karyotyping by high-resolution SNP array, we obtained data on ROHs/LCSHs from 772 children with neurodevelopmental disorders and congenital malformations. ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 were additionally analyzed by original bioinformatic approaches to uncover the pathogenic value. Results: ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 were detected in 67 (8.7%) individuals. Bioinformatic analyses demonstrated that ROHs/LCSHs affecting imprinted loci of chromosome 7 are not associated with clearly recognizable outcomes. Alternatively, ROHs/LCSHs affecting imprinted loci of chromosome 11 (11p15.5p15.4; Beckwith-Wiedemann syndrome) and chromosome 15 (15q11.2; Prader-Willi/Angelman syndromes) were associated with distinct outcomes as shown by bioinformatics approaches. Prader-Willi/Angelman syndrome loci were affected in 18 cases (2.3%), whereas Beckwith-Wiedemann syndrome loci were affected in 10 cases (1.3%). Conclusion: Analysis of the outcomes of ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 has demonstrated that the epigenomic changes affecting 11p15.5p15.4, and 15q11.2 (28 cases; 3.6%) are associated with atypical forms of Beckwith-Wiedemann and Prader-Willi/Angelman syndromes, respectively. The outcomesof ROHs/LCSHs in chromosome 7 have not been found convincing for a definitive conclusion about the phenotypic effects. Molecular karyotyping by SNP array is a valuable diagnostic technique offering opportunities for detecting these common but underestimated epigenetic causes for neurodevelopmental disorders and congenital malformations.

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