Altered chromatin topologies caused by balanced chromosomal translocation lead to central iris hypoplasia

Wenmin Sun, Dan Xiong, Jiamin Ouyang, Xueshan Xiao, Yi Jiang, Yingwei Wang, Shiqiang Li, Ziying Xie, Junwen Wang, Zhonghui Tang () and Qingjiong Zhang ()
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Wenmin Sun: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Dan Xiong: Sun Yat-sen University
Jiamin Ouyang: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Xueshan Xiao: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Yi Jiang: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Yingwei Wang: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Shiqiang Li: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Ziying Xie: Sun Yat-sen University
Junwen Wang: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science
Zhonghui Tang: Sun Yat-sen University
Qingjiong Zhang: Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.

Date: 2024
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DOI: 10.1038/s41467-024-49376-w

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