講演情報
[S9-1]Clinical Cytogenetics in the Era of the 3D Genome
○Cynthia C. Morton1, Ibrahim Alkuraya2, Abna Ajeesh2, Elijah Mena3, Rebecca Andersen4, Matthew Chau5, Zirui Dong5, Richard Choy5, Hila Romi2 (1.Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA, 2.Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, USA, 3.Department of Genetics, Harvard Medical School, Boston, USA, 4.Division of Genetics and Genomics, Boston Children’s Hospital, Boston, USA, 5.Department of Obstetrics and Gynecology, Chinese University of Hong Kong, HongKong, China)
Since recognition of the correct number of chromosomes in humans, chromosomal abnormalities have been foundational in annotating the human genome. Evolving knowledge of the human genome reveals elements of the noncoding genome such as micro RNAs and long non-coding RNAs (lncRNAs) that will doubtless contribute to a more precise understanding of gene expression in human biology, and chromosomal structural rearrangements will provide signposts for their investigation.
The Developmental Genome Anatomy Project (DGAP) has championed nucleotide precision analyses of balanced chromosomal rearrangements in the setting of clinical phenotypes. Initially focused on gene disruptions, it became increasingly clear that 3D organization underlies position effects on protein-coding genes. A mother-daughter pair were referred to DGAP with nonsyndromic mild-to-moderate sensorineural hearing loss and a 46,XX,t(14;17)(q24.3;q23) mat.seq[GRCh37]t(14;17)(14pter→14q23.3(66,322,078)::17q23.2(59,471,205)→17qter;17pter→17q23.2(59,471,173)::TATATACC::14q23.3(66,322,077)→14qter), resulting in disruption of antisense lncRNA TBX2-AS1 in intron 1 at 17q32.2 on the negative strand 136 base pairs upstream of TBX2 on the positive strand. TBX2 is required for cochlear development in mice and upon ablation of TBX2, inner hair cells are replaced with outer hair cells. TBX2-AS1 disruption with loss of function predicted from the translocated allele may result in dysregulated TBX2 expression. 3D genome analysis of DGAP cases indicates potential for identification of lncRNAs as etiologic in clinical disorders.
The Developmental Genome Anatomy Project (DGAP) has championed nucleotide precision analyses of balanced chromosomal rearrangements in the setting of clinical phenotypes. Initially focused on gene disruptions, it became increasingly clear that 3D organization underlies position effects on protein-coding genes. A mother-daughter pair were referred to DGAP with nonsyndromic mild-to-moderate sensorineural hearing loss and a 46,XX,t(14;17)(q24.3;q23) mat.seq[GRCh37]t(14;17)(14pter→14q23.3(66,322,078)::17q23.2(59,471,205)→17qter;17pter→17q23.2(59,471,173)::TATATACC::14q23.3(66,322,077)→14qter), resulting in disruption of antisense lncRNA TBX2-AS1 in intron 1 at 17q32.2 on the negative strand 136 base pairs upstream of TBX2 on the positive strand. TBX2 is required for cochlear development in mice and upon ablation of TBX2, inner hair cells are replaced with outer hair cells. TBX2-AS1 disruption with loss of function predicted from the translocated allele may result in dysregulated TBX2 expression. 3D genome analysis of DGAP cases indicates potential for identification of lncRNAs as etiologic in clinical disorders.