Cone-rod dystrophy associated with novel variations on <i>CDHR1</i> and <i>C2orf71</i> gene_Chinese Journal of Ocular Fundus Diseases

Authors：

Hu Xuejun ¹ , Li Zhen ¹ , Niu Wei ¹ , Yang Shangying ¹ , Rui Xue ² , Sheng Xunlun ^1,2 ,  Rong Weining ¹

1. Ningxia Eye Hospital, People' Hospital of Ningxia Hui Automous Region, Fist Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye, Ningxia 750001, China;
2. Gansu Aier Optometry Hospital, Lanzhou 730050, China;
Hu Xuejun and Li Zhen are contributed equally to the article;

Corresponding?author：

Rong Weining, Email: rongweining426@126.com

Keywords：

Cone-rod dystrophy; CDHR1 gene; C2orf71 gene; Mutation

DOI：

10.3760/cma.j.cn511434-20211213-00695

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Objective To observe and analyze the gene mutation and clinical phenotype of patients with cone and rod dystrophy (CORD). Methods A pedigree investigarion. Two CORD pedigrees including 2 patients and 6 family members were enrolled in Ningxia Eye Hospital of People' Hospital of Ningxia Hui Automous Region for this study. The patients were from 2 unrelated families, all of whom were probands. Take medical history with best-corrected visual acuity (BCVA), color vision, slit lamp microscopy, indirect ophthalmoscopy, fundus color photography, optical coherence tomography (OCT), autofluorescence (AF), fluorescein fundus angiography (FFA), electroretinogram (ERG). The peripheral venous blood of patients and their parents was collected, whole genome DNA was extracted, Trio whole genome exome sequencing was performed, Sanger verification and pedigree co-segregation were performed for suspected pathogenic mutation sites. According to the law of inheritance, family history was analyzed to establish its genetic type. Mutational loci pathogenicity was analyzed according to the American College of Medical Genetics (ACMG) guidelines and 4 online tools. Results Two CORD families showed autosomal recessive inheritance. The proband of pedigree 1 was female, 49 years old. Binocular vision loss with photophobia lasted for 9 years and night blindness for 4 years. The BCVA of right eye and left eye were 0.03 and 0.06, respectively. The results of ERG showed that the amplitudes of dark adaptation 0.01 b-wave and dark adaptation 3.0 a-wave and b-wave in both eyes were slightly decreased, and the amplitudes of light adaptation 3.0 a-wave and b-wave were severely decreased. The proband of pedigree 2 was male, 30 years old. Vision loss in both eyes for 4 years. Denying a history of night blindness. The BCVA of right eye and left eye were 0.3 and 0.2, respectively. The results of ERG showed that the amplitudes of dark adaptation 0.01 b-wave and dark adaptation 3.0 a-wave and b-wave in both eyes were slightly decreased, and the amplitudes of light adaptation 3.0 a-wave and b-wave were severely decreased. The color of optic disc in both eyes was light red, the macular area was atrophic, the foveal reflection disappeared, and the peripheral retina was punctate pigmentation. The main fundus changes in 2 patients were macular atrophy. The proband of pedigree 1 carried compound heterozygous variations c.439-2A>G (M1) and c.676delT (p.F226fs) (M2) on CDHR1 gene. Her father and mother carried M2 and M1 heterozygous mutations, respectively. The proband of pedigree 2 carried compound heterozygous variations c.2665dupC (p.L889fs) (M3) and c.878T>C (p.L293P) (M4) on C2orf71 gene. His father and mother carried M4 and M3 heterozygous mutations, respectively. According to ACMG guidelines and on line tools, 4 variations were considered as pathogenic level. Conclusions M1 and M2 of CDHR1 gene and M3 and M4 of C2orf71 gene are new pathogenic mutations of CORD. All patients presented with the clinical phenotype of decreased visual acuity and macular atrophy.

Citation： Hu Xuejun, Li Zhen, Niu Wei, Yang Shangying, Rui Xue, Sheng Xunlun, Rong Weining. Cone-rod dystrophy associated with novel variations on CDHR1 and C2orf71 gene. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 656-662. doi: 10.3760/cma.j.cn511434-20211213-00695 Copy

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9.	Henderson RH, Li Z, Abd El Aziz MM, et al. Biallelic mutation of protocadherin-21 (PCDH21) causes retinal degeneration in humans[J]. Mol Vis, 2010, 16: 46-52.
10.	Fu J, Ma L, Cheng J, et al. A novel, homozygous nonsense variant of the CDHR1 gene in a Chinese family causes autosomal recessive retinal dystrophy by NGS-based genetic diagnosis[J]. J Cell Mol Med, 2018, 22(11): 5662-5669. DOI: 10.1111/jcmm.13841.
11.	Stingl K, Mayer AK, Llavona P, et al. CDHR1 mutations in retinal dystrophies[J/OL]. Sci Rep, 2017, 7(1): 6992[2017-08-01]. https://pubmed.ncbi.nlm.nih.gov/28765526/. DOI: 10.1038/s41598-017-07117-8.
12.	Haque MN, Kurata K, Hosono K, et al. A Japanese family with cone-rod dystrophy of delayed onset caused by a compound heterozygous combination of novel CDHR1 frameshift and known missense variants[J]. Hum Genome Var, 2019, 6: 18. DOI: 10.1038/s41439-019-0048-8.
13.	Gerth-Kahlert C, Tiwari A, Hanson JVM, et al. C2orf71 mutations as a frequent cause of autosomal-recessive retinitis pigmentosa: clinical analysis and presentation of 8 novel mutations[J]. Investig Opthalmology Vis Sci, 2017, 58(10): 3840-3850. DOI: 10.1167/iovs.17-21597.
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15.	Collin RW, Safieh C, Littink KW, et al. Mutations in C2ORF71 cause autosomal recessive retinitis pigmentosa[J]. Am J Hum Genet, 2010, 86(5): 783-788. DOI: 10.1016/j.ajhg.2010.03.016.
16.	Serra R, Floris M, Pinna A, et al. Novel mutations in c2orf71 causing an early onset form of cone rod dystrophy: a molecular diagnosis after 20 years of clinical follow-up[J]. Mol Vis, 2019, 25: 814-820.

1. Tsang SH, Sharma T. Progressive cone dystrophy and cone-rod dystrophy (XL, AD, and AR)[J]. Adv Exp Med Biol, 2018, 1085: 53-60. DOI: 10.1007/978-3-319-95046-4_12.
2. Hamel CP. Cone rod dystrophies[J]. Orphanet J Rare Dis, 2007, 2: 7. DOI: 10.1186/1750-1172-2-7.
3. 盛迅倫. 視錐細胞營養不良和視錐-視桿細胞營養不良[M]//盛迅倫, 莊文娟. 遺傳性眼病的基礎與臨床. 北京: 人民衛生出版社, 2019: 120-122.Sheng XL. Cone dystroph and cone-rod dystrophy[M]//Sheng XL, Zhuang WJ. Foundation and clinic of hereditary eye diseases. Beijing: People's Medical Publishing House, 2019: 120-122.
4. Nakajima D, Nakayama M, Kikuno R, et al. Identifification of three novel non-classical cadherin genes through comprehensive analysis of large cDNAs[J]. Brain Res Mol Brain Res, 2001, 94(1-2): 85-95. DOI: 10.1016/s0169-328x(01)00218-2.
5. Sharon D, Blackshaw S, Cepko CL, et al. Profifile of the genes expressed in the human peripheral retina, macula, and retinal pigment epithelium determined through serial analysis of gene expression (SAGE)[J]. Proc Natl Acad Sci USA, 2002, 99(1): 315-320. DOI: 10.1073/pnas.012582799.
6. Rattner A, Chen J, Nathans J. Proteolytic shedding of the extracellular domain of photoreceptor cadherin Implications for outer segment assembly[J]. J Biol Chem, 2004, 279(40): 42202-42210. DOI: 10.1074/jbc.M407928200.
7. Rattner A, Smallwood PM, Williams J, et al. A photoreceptor- specifific cadherin is essential for the structural integrity of the outer segment and for photoreceptor survival[J]. Neuron, 2001, 6,32(5): 775-786. DOI: 10.1016/s0896-6273(01)00531-1.
8. Ostergaard E, Batbayli M, Duno M, et al. Mutations in PCDH21 cause autosomal-recessive cone-rod dystrophy[J]. J Med Genet, 2010, 47(10): 665-669. DOI: 10.1136/jmg.2009.069120.
9. Henderson RH, Li Z, Abd El Aziz MM, et al. Biallelic mutation of protocadherin-21 (PCDH21) causes retinal degeneration in humans[J]. Mol Vis, 2010, 16: 46-52.
10. Fu J, Ma L, Cheng J, et al. A novel, homozygous nonsense variant of the CDHR1 gene in a Chinese family causes autosomal recessive retinal dystrophy by NGS-based genetic diagnosis[J]. J Cell Mol Med, 2018, 22(11): 5662-5669. DOI: 10.1111/jcmm.13841.
11. Stingl K, Mayer AK, Llavona P, et al. CDHR1 mutations in retinal dystrophies[J/OL]. Sci Rep, 2017, 7(1): 6992[2017-08-01]. https://pubmed.ncbi.nlm.nih.gov/28765526/. DOI: 10.1038/s41598-017-07117-8.
12. Haque MN, Kurata K, Hosono K, et al. A Japanese family with cone-rod dystrophy of delayed onset caused by a compound heterozygous combination of novel CDHR1 frameshift and known missense variants[J]. Hum Genome Var, 2019, 6: 18. DOI: 10.1038/s41439-019-0048-8.
13. Gerth-Kahlert C, Tiwari A, Hanson JVM, et al. C2orf71 mutations as a frequent cause of autosomal-recessive retinitis pigmentosa: clinical analysis and presentation of 8 novel mutations[J]. Investig Opthalmology Vis Sci, 2017, 58(10): 3840-3850. DOI: 10.1167/iovs.17-21597.
14. Corral-Serrano JC, Lamers IJC, et al. PCARE and WASF3 regulate ciliary F-actin assembly that is required for the initiation of photoreceptor outer segment disk formation[J]. Proc Natl Acad Sci USA, 2020, 117(18): 9922-9931. DOI: 10.1073/pnas.1903125117.
15. Collin RW, Safieh C, Littink KW, et al. Mutations in C2ORF71 cause autosomal recessive retinitis pigmentosa[J]. Am J Hum Genet, 2010, 86(5): 783-788. DOI: 10.1016/j.ajhg.2010.03.016.
16. Serra R, Floris M, Pinna A, et al. Novel mutations in c2orf71 causing an early onset form of cone rod dystrophy: a molecular diagnosis after 20 years of clinical follow-up[J]. Mol Vis, 2019, 25: 814-820.

Chinese Journal of Ocular Fundus Diseases

Cone-rod dystrophy associated with novel variations on CDHR1 and C2orf71 gene

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