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

Author

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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)

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.

Suggested Citation

  • Wenmin Sun & Dan Xiong & Jiamin Ouyang & Xueshan Xiao & Yi Jiang & Yingwei Wang & Shiqiang Li & Ziying Xie & Junwen Wang & Zhonghui Tang & Qingjiong Zhang, 2024. "Altered chromatin topologies caused by balanced chromosomal translocation lead to central iris hypoplasia," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49376-w
    DOI: 10.1038/s41467-024-49376-w
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    References listed on IDEAS

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    1. John Arne Dahl & Inkyung Jung & Håvard Aanes & Gareth D. Greggains & Adeel Manaf & Mads Lerdrup & Guoqiang Li & Samantha Kuan & Bin Li & Ah Young Lee & Sebastian Preissl & Ingunn Jermstad & Mads Haugl, 2016. "Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition," Nature, Nature, vol. 537(7621), pages 548-552, September.
    2. Yutaka Shimomura & Dritan Agalliu & Alin Vonica & Victor Luria & Muhammad Wajid & Alessandra Baumer & Serena Belli & Lynn Petukhova & Albert Schinzel & Ali H. Brivanlou & Ben A. Barres & Angela M. Chr, 2010. "APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex," Nature, Nature, vol. 464(7291), pages 1043-1047, April.
    3. Lukas Gerasimavicius & Benjamin J. Livesey & Joseph A. Marsh, 2022. "Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Ryan L. Collins & Harrison Brand & Konrad J. Karczewski & Xuefang Zhao & Jessica Alföldi & Laurent C. Francioli & Amit V. Khera & Chelsea Lowther & Laura D. Gauthier & Harold Wang & Nicholas A. Watts , 2020. "A structural variation reference for medical and population genetics," Nature, Nature, vol. 581(7809), pages 444-451, May.
    5. Carles A. Boix & Benjamin T. James & Yongjin P. Park & Wouter Meuleman & Manolis Kellis, 2021. "Regulatory genomic circuitry of human disease loci by integrative epigenomics," Nature, Nature, vol. 590(7845), pages 300-307, February.
    6. Ernest Turro & William J. Astle & Karyn Megy & Stefan Gräf & Daniel Greene & Olga Shamardina & Hana Lango Allen & Alba Sanchis-Juan & Mattia Frontini & Chantal Thys & Jonathan Stephens & Rutendo Mapet, 2020. "Whole-genome sequencing of patients with rare diseases in a national health system," Nature, Nature, vol. 583(7814), pages 96-102, July.
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