74. Genetic and functional characterization of complex chromosomal rearrangements in a family with multisystem anomalies

Aly Abdelkareem

He Fang

I am a Laboratory Genetics and Genomics Fellow at University of Washington. I have been engaged in genetic and epigenetics research and my research achievements have contributed to understanding the biology of genetic disorders that affect the general public. My Ph.D. work on decrypting the structural dynamics of linker histone has revealed its role in shaping epigenetic landscapes and has provided keen scientific insights into disease-related epigenetic changes. I then conducted my postdoctoral research on X chromosome inactivation and sex differences. As a Laboratory Genetics and Genomics Fellow, I am currently actively engaged in validation and implementation of new laboratory methods in clinical services. I will continue to build on my previous training in genetics and genomics and apply my expertise to molecular diagnosis of human disease in clinical settings.


He Fang, Whitney Neufeld-Kaiser, Yajuan Liu

University of Washington, Seattle, WA, USA

Complex chromosomal rearrangements (CCRs) are rare structural variants which involve three or more chromosomal breakpoints and are usually de novo in most reported cases. Traditional molecular cytogenetics approaches using karyotyping, fluorescence in situ hybridization (FISH) and chromosome microarray analysis (CMA) have been used clinically to diagnose CCRs. However, each of these standard tests has limitations, including low resolution causing difficulty in detecting cryptic rearrangements, imprecise breakpoint mapping, or inability to detect balanced rearrangements. We present here a family whose inherited CCRs were evaluated using karyotyping, FISH, CMA, and two novel methods, optical genome mapping (OGM) and proximity ligation sequencing (Hi-C). The indication for testing in the proband was significant intellectual disability and an immune deficiency. Her mother was unaffected. Karyotype and FISH analysis identified a CCR with at least 4 breakpoints in the proband and 7 breakpoints in her mother involving chromosomes 1, 7 and 11. CMA showed a duplication of 7pter-p22 and 3 deletions of 1q44, 7q11 and 11q25 in the proband but a balanced genome in her mother. Both OGM and Hi-C defined the breakpoints of CCR in the proband and her mother at higher resolution than the more traditional test methods. The comparison of these platforms for cytogenetic and genomic characterization of CCRs will be discussed. We also performed transcriptome and methylome analyses of this family, and the biological pathways affected by the CCRs will be discussed.