Isolated ocular colobomas caused by a novel variant of the <i>YAP1</i> gene_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Jie , Guo Xiaohong , Xing Yasi , Lu Xiaonan ,  Dai Shuzhen

Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan Eye Hospital, Henan Eye Institute, Zhengzhou, Henan 450003, China;

Corresponding author：

Dai Shuzhen, Email: dsz997300056@163.com

Keywords：

Isolated ocular colobomas; YAP1 gene; Genotype; Phenotype

DOI：

10.3760/cma.j.cn511434-20220818-00459

Video：

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Objective To identify the causative gene and observe the phenotypic characteristics of a family with isolated microphthalmia-anophthalmia-coloboma (MAC). Methods A retrospective clinical study. One patient (proband) and 3 family members of a family with MAC visited the Henan Eye Hospital from May 2019 to May 2022 were included in the study. The patient's medical history and family history were inquired in detail, and the best corrected visual acuity (BCVA), slit lamp microscope, fundus photography, optical coherence tomography (OCT), ophthalmological B mode ultrasound and axial length (AL) measurement were performed. The peripheral venous blood of the proband, his parents and brother was collected for Trio whole-exome sequencing and pathogenic gene screening. Fluorescence quantitative Polymerase chain reaction was used to verify the suspicious variations. The clinical features of the patient's ocular and systemic also were observed. Results The proband, male, was 3 years old at the first visit. The horizontal pendular nystagmus was detected in both eyes. Vertical elliptical microcornea and keyhole-shaped iris colobomas were detected in both eyes. The objective refraction at first visit (3 years old) was －4.00 DS/－0.50 DC×105° (OD) and －3.50 DS/－1.25 DC×80° (OS). Refraction and BCVA at 6 years old: －6.50 DS/－2.00 DC×110°→0.05 (OD) and －6.00 DS/－1.50 DC×80°→0.2 (OS). The AL at 4 years and 10 months old was 24.62 mm (OD) and 23.92 mm (OS), respectively. The AL at 5 years and 7 months old was 25.24 mm (OD) and 24.36 mm (OS), respectively. Ultrasonography shows tissue defects in both eyes. Fundus photography showed the inferior choroidal coloboma involving optic disc. OCT showed the optic disc in both eyes was abnormal with colobomas around, and the retinal neurosensory layer in colobomas area was disordered and thin; the retinoschisis was visible in the left eye. The proband's parents and siblings have normal phenotypes. Whole exome sequencing reveals a denovo heterozygous deletion of YAP1 gene: YAP1, chr11: 10280247-102100671, NM_ 001130145, loss 1 (EXON: 6-9). The results of bioinformatics analysis were pathogenic variants. Parents and siblings were of the wild type. Conclusions Loss of heterozygosity in exons 6-9 of YAP1 gene is the pathogenic variation in this family. It can cause abnormal development of anterior segment, chorioretinal colobomas, deepening of axial myopia, even severe macular colobomas and retinoschisis.

Citation： Li Jie, Guo Xiaohong, Xing Yasi, Lu Xiaonan, Dai Shuzhen. Isolated ocular colobomas caused by a novel variant of the YAP1 gene. Chinese Journal of Ocular Fundus Diseases, 2023, 39(7): 544-548. doi: 10.3760/cma.j.cn511434-20220818-00459 Copy

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13.	Lima Cunha D, Arno G, Corton M, et alThe spectrum of PAX6 mutations and genotype-phenotype correlations in the eye[J]. Genes (Basel)201910121050. DOI:10.3390/genes10121050.
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1. Tibrewal S, Subhedar K, Sen P, et alClinical spectrum of non-syndromic microphthalmos, anophthalmos and coloboma in the paediatric population: a multicentric study from North India[J]. Br J Ophthalmol20211057897903. DOI:10.1136/bjophthalmol-2020-316910.
2. Harding P, Moosajee MThe molecular basis of human anophthalmia and microphthalmia[J]. J Dev Biol20197316. DOI:10.3390/jdb7030016.
3. Williamson KA, Rainger J, Floyd JA, et al. Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects[J]. Am J Hum Genet2014942295302. DOI:10.1016/j.ajhg.2014.01.001.
4. Richards S, Aziz N, Bale S, et alACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med2015175405424. DOI:10.1038/gim.2015.30.
5. Basu-Roy U, Bayin NS, Rattanakorn K, et alSox2 antagonizes the Hippo pathway to maintain stemness in cancer cells[J]. Nat Commun201566411. DOI:10.1038/ncomms7411.
6. Hauri S, Wepf A, van Drogen A, et alInteraction proteome of human Hippo signaling: modular control of the co-activator YAP1[J]. Mol Syst Biol20139713. DOI:10.1002/msb.201304750.
7. Miesfeld JB, Gestri G, Clark BS, et alYap and Taz regulate retinal pigment epithelial cell fate[J]. Development20151421730213032. DOI:10.1242/dev.119008.
8. Seo E, Basu-Roy U, Gunaratne PH, et alSOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteo-adipo lineage[J]. Cell Rep20133620752087. DOI:10.1016/j.celrep.2013.05.029.
9. Oatts JT, Hull S, Michaelides M, et al. Novel heterozygous mutation in YAP1 in a family with isolated ocular colobomas[J]. Ophthalmic Genet2017383281283. DOI:10.1080/13816810.2016.1188122.
10. Holt R, Ceroni F, Bax DA, et al. New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders[J]. Sci Rep2017717975. DOI:10.1038/s41598-017-08397-w.
11. Fossdal R, Jonasson F, Kristjansdottir GT, et alA novel TEAD1 mutation is the causative allele in Sveinsson's chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration)[J]. Hum Mol Genet2004139975981. DOI:10.1093/hmg/ddh106.
12. Williamson KA, FitzPatrick DRThe genetic architecture of microphthalmia, anophthalmia and coloboma[J]. Eur J Med Genet2014578369380. DOI:10.1016/j.ejmg.2014.05.002.
13. Lima Cunha D, Arno G, Corton M, et alThe spectrum of PAX6 mutations and genotype-phenotype correlations in the eye[J]. Genes (Basel)201910121050. DOI:10.3390/genes10121050.
14. 李杰, 栗占荣, 邢亚斯, 等先天性无虹膜患者的基因型-表型分析[J]. 中华实验眼科杂志20193711896900. DOI:10.3760/cma.j.issn.2095-0160.2019.11.009..Li J, Li ZR, Xing YS, et alGenetic screening of the congenital aniridia and genotype-phenotype analysis[J]. Chin J Exp Ophthalmol20193711896900. DOI:10.3760/cma.j.issn.2095-0160.2019.11.009.
15. Morrison D, FitzPatrick D, Hanson I, et alNational study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology[J]. J Med Genet20023911622. DOI:10.1136/jmg.39.1.16.
16. Kumar K, Tanwar M, Naithani P, et alPAX6 gene analysis in irido-fundal coloboma[J]. Mol Vis20111714141419.
17. Ohuchi H, Sato K, Habuta M, et alCongenital eye anomalies: more mosaic than thought? [J]. Congenit Anom (Kyoto)20195935673. DOI:10.1111/cga.12304.
18. Hotta K, Hirakata A, Hida TRetinoschisis associated with disc coloboma[J]. Br J Ophthalmol1999831124. DOI:10.1136/bjo.83.1.123b.
19. Roy R, Waanbah AD, Mathur G, et alOptical coherence tomography characteristics in eyes with optic pit maculopathy[J]. Retina2013334771775. DOI:10.1097/IAE.0b013e31826f5234.
20. Lingam G, Sen AC, Lingam V, et alOcular coloboma-a comprehensive review for the clinician[J]. Eye (Lond)202135820862109. DOI:10.1038/s41433-021-01501-5.

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Isolated ocular colobomas caused by a novel variant of the YAP1 gene

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