Background We report here clinical, cytogenetic and molecular data for a pair of monochorionic diamniotic twins with paternal isodisomy for chromosome 19. Both twins presented with dysmorphic features and global developmental delay. This represents, to our knowledge, the first individual human case of paternal uniparental disomy for chromosome 19 (UPD19).
Methods Whole-exome sequencing, together with conventional karyotype and SNP array analysis were performed along with genome-wide DNA methylation array for delineation of the underlying molecular defects.
Results Conventional karyotyping on amniocytes and lymphocytes showed normal karyotypes for both twins. Whole-exome sequencing did not identify any pathogenic sequence variants but >5000 homozygous exonic variants on chromosome 19, suggestive of UPD19. SNP arrays on blood and buccal DNA both showed paternal isodisomy for chromosome 19. Losses of imprinting for known imprinted genes on chromosome 19 were identified, including ZNF331, PEG3, ZIM2 and MIMT1. In addition, imprinting defects were also identified in genes located on other chromosomes, including GPR1-AS, JAKMP1 and NHP2L1.
Conclusion Imprinting defects are the most likely cause for the dysmorphism and developmental delay in this first report of monozygotic twins with UPD19. However, epigenotype-phenotype correlation will require identification of additional individuals with UPD19 and further molecular analysis.
- uniparental sisomy
- paternal upd
- dna methylation
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Contributors RAW and BHYC conceived and supervised the study. KSY and MSPH drafted the manuscript. SLL, ASYK, MHYT, PLS and BHYC recruited and managed the patients. KSY, MSPH, SLL, ASYK, MHYT, KYKC, CCYM, PLS, GKCL, RP, CRM, SWS and SC analysed and interpreted the data. SLL, ASYK, SWS, RAW and BHYC provided facilities and resources for the study. All authors read the manuscript, revised it critically for important intellectual content and approved the final manuscript.
Funding BHYC is funded by the Society for the Relief of Disabled Children and Medix. SWS is funded by the GlaxoSmithKline/ Canadian Institute of Health Research Chair in the Genome Sciences at the University of Toronto and The Hospital for Sick Children.
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 12–211).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Not applicable.