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Abstract
Microtia-anotia is a common congenital anomaly. In most cases, the genetic etiology remains unknown. The proper development of outer ear is closely related to cranial neural crest cells. Abnormal DNA recombination perturbing the function of long-range enhancers can lead to genomic disorder. Previously, we identified 4p16.1 duplications in microtia patients and revealed the enhancer function of an evolutionarily conserved region (ECR). Here we recruited additional patients and attempted to identify the minimal overlapping region and regulatory elements. We identified five individuals (F6-F10 probands) with 4p16.1 duplication. The duplications in F3 and F5 were refined to 192.6 kb and 96.1 kb. Precise junction breakpoints in F4 and F6-F10 were detected. The minimal overlapping region (chr4: 8,689,510–8712,827, hg19) contained conserved sequences in addition to ECR. Dual-luciferase assays detected enhancer activity in the TFAP2C binding and 1794 sequence. We present five additional cases of concha-type microtia with 4p16.1 duplication. The minimal overlapping region contains regulatory elements that function as in-cis tissue-specific modules, regulating downstream gene expression during development of cranial neural crest cell.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- ECR:
Evolutionarily conserved region
- iNCCs:
Induced neural crese cells
- OCACS:
Oculoauricular syndrome
- CFM:
Craniofacial microsomia
- PRS:
Pierre Robin sequence
- CNCC:
Cranial neural crest cell
- TF:
Transcription factors
- WGS:
Whole genome sequencing
- CNVs:
Copy number variation
- SV:
Structural variation
- MAF:
Minor allele frequency
- gnomAD:
Genome Aggregation Database
- aCGH:
Array comparative genomic hybridization
- ONT:
Oxford Nanopore Technology
- qPCR:
Quantitative real-time polymerase chain reaction
- RCN:
Relative copy number
- hNCC:
Human neural crest cell
- iPSC:
Induced pluripotent stem cell
- SD:
Segment duplication
- SINE:
Short interspersed nuclear elements
- LINE:
Long interspersed nuclear elements
- LTR:
Long terminal repeat elements
- DNA:
DNA repeat elements
- ESC:
Embryonic stem cell
- WHS:
Wolf–Hirschhorn syndrome
- LCR:
Low-copy repeats
- NHEJ:
Nonhomologous end ligation
- RBMs:
Replication-based mechanisms
- MMBIR:
Microhomology-mediated break-induced replication
- FoSTeS:
Forehead stalling and template switching
- CRMs:
Cis-regulatory modules
- CNEs:
Conserved non-coding elements
- TAD:
Topologically associated domain
- SNVs:
Single nucleotide variations
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Acknowledgements
We thank all participants in the study.
Funding
This work was supported by the Fund of Plastic Surgery Hospital, Chinese Academy of Medical Sciences (No.YS202036) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No.2021-I2M-1-052).
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Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, China
Xiaolu Meng, Jiawei Du, Bo Pan, Nuo Si & Haiyue Jiang
Laboratory of Clinical Genetics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
Zhe Liu
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- Jiawei Du
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- Zhe Liu
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- Nuo Si
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X.M. and N.S. conceived and designed the study. B.P. and H.J. analyzed and interpreted the clinical data. Z.L. and N.S. designed the custom array and performed the aCGH assay. X.M., J.D. and N.S. performed the genetic analysis. X.M. and J.D. performed the PCR and cellular experiments. X.M. and N.S. wrote the manuscript. B.P. and H.J. contributed to supervision. N.S. and H.J. contributed to funding acquisition. All authors read and approved the final manuscript.
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Meng, X., Du, J., Liu, Z.et al. Non-recurrent duplications on chromosome 4p16.1 involving cis-regulatory elements affecting neural crest development in patients with isolated bilateral microtia.Hum. Genet.144, 1215–1227 (2025). https://doi.org/10.1007/s00439-025-02788-0
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