Analysis of ocular clinical features and gene mutations of Waardenburg syndrome_Chinese Journal of Ocular Fundus Diseases

Authors：

Chen Qin , She Kaiqin , Jiang Shanming ,  Lu Fang

Department of Ophthalmology, West China Hospital Sichuan University, Chengdu, 610041;

Corresponding author：

Lu Fang, Email: lufang@wchscu.cn

Keywords：

Waardenburg's syndrome; Genes; Mutation; Iris; Fundus oculi

DOI：

10.3760/cma.j.cn511434-20211116-00642

Video：

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Objective To deeply explore the clinical features and gene mutations of Waardenburg syndrome (WS) by tested of the eyes and genes of three patients. Methods A Case series study. From 2019 to 2021, 3 children with WS who were diagnosed at Department of Ophthalmology, West China Hospital of Sichuan University were included in the study. Among them, there were 2 males and 1 female; the ages were 3, 4, and 12 months, respectively. All children underwent external eye, anterior segment, fundus and fluorescein fundus angiography, the clinical features of the eyes were observed. The peripheral venous blood of 3 children was collected, and the whole genome DNA was extracted for whole exome sequencing to analyze the gene mutation sites. Results All children had different degrees of iris heterochromia and fundus pigment abnormalities, and were accompanied by sensorineural hearing impairment. Case 1 had dystopia canthorum; case 2 had macular fovea hypoplasia. The sequencing results of case 1 showed that there were large fragments of heterozygous deletion in exons 2-8 of the Paired box 3 (PAX3) gene, who was diagnosed as WS Ⅰ type. The sequencing results of of case 2 showed heterozygous mutation in exon 9 of Microphthalmia-associated transcription factor (MITF) gene (c.1066 C＞T), combined with heterozygous mutation in exon 1 of HPS6 gene (c.1417 G＞T), who was diagnosed as WS Ⅱ type. The sequencing result of case 3 showed that the exon 3 of SOX10 gene had loss of heterozygosity (c.497_500 delAAGA), who was diagnosed as WS Ⅳ type. Both PAX3 and SOX10 gene mutations were newly discovered mutations. Conclusions The ocular clinical features of Waardenburg syndrome include hypopigmentation of the iris and choroid, and dystopia canthorum, etc. Early screening of the eye and hearing will help to better diagnose the disease. The large fragments of heterozygous deletion in exons 2-8 of the PAX3 gene, the heterozygous mutation in exon 9 of MITF gene (c.1066 C＞T), and the loss of heterozygosity in exon 3 of SOX10 gene are pathogenic genetic variations of 3 children.

Citation： Chen Qin, She Kaiqin, Jiang Shanming, Lu Fang. Analysis of ocular clinical features and gene mutations of Waardenburg syndrome. Chinese Journal of Ocular Fundus Diseases, 2021, 37(12): 954-959. doi: 10.3760/cma.j.cn511434-20211116-00642 Copy

1.	Ahmed Jan N, Mui RK, Masood S. Waardenburg syndrome[M]. StatPearls[Internet]: Treasure Island (FL), 2021. https://www.ncbi.nlm.nih.gov/books/NBK560879/.
2.	Newton V. Hearing loss and Waardenburg's syndrome: implications for genetic counselling[J]. J Laryngol Otol, 1990, 104(2): 97-103. DOI: 10.1017/s002221510011196x.
3.	Pingault V, Ente D, Dastot-Le Moal F, et al. Review and update of mutations causing Waardenburg syndrome[J]. Hum Mutat, 2010, 31(4): 391-406. DOI: 10.1002/humu.21211.
4.	Nicole LD, Chaya K. The neural crest[M]. 2nd ed. London: Cambridge University Press, 1999: 24-27.
5.	Read AP, Newton VE. Waardenburg syndrome[J]. J Med Genet, 1997, 34(8): 656-665. DOI: 10.1136/jmg.34.8.656.
6.	Bocángel MAP, Melo US, Alves LU, et al. Waardenburg syndrome: novel mutations in a large Brazilian sample[J]. Eur J Med Genet, 2018, 61(6): 348-354. DOI: 10.1016/j.ejmg.2018.01.012.
7.	Liu Y, Pan H, Wang J, et al. Ophthalmological features and treatments in five cases of Waardenburg syndrome[J]. Exp Ther Med, 2020, 20(4): 3072-3077. DOI: 10.3892/etm.2020.9035.
8.	Tang XJ, Ping XY, Luo CQ, et al. Dystrophia canthorum in Waardenburg syndrome with a novel MITF mutation[J]. Int J Ophthalmol, 2020, 13(7): 1054-1059. DOI: 10.18240/ijo.2020.07.06.
9.	Vichare N, Bhargava N. Waardenburg syndrome: a rare case with bilateral congenital cataract: an unusual entity[J]. Med J Armed Forces India, 2013, 69(2): 172-174. DOI: 10.1016/j.mjafi.2012.02.017.
10.	Cortés-González V, Zenteno JC, Guzmán-Sánchez M, et al. Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations[J]. Am J Med Genet A, 2016, 170(12): 3294-3297. DOI: 10.1002/ajmg.a.37937.
11.	Shields CL, Nickerson SJ, Al-Dahmash S, et al. Waardenburg syndrome: iris and choroidal hypopigmentation[J]. JAMA Ophthalmol, 2013, 131(9): 1167-1173. DOI: 10.1001/jamaophthalmol.2013.4190.
12.	Mullaney PB, Parsons MA, Weatherhead RG, et al. Clinical and morphological features of Waardenburg syndrome type Ⅱ[J]. Eye (Lond), 1998, 12 (Pt 3a): 353-357. DOI: 10.1038/eye.1998.85.
13.	Planque N, Raposo G, Leconte L, et al. Microphthalmia transcription factor induces both retinal pigmented epithelium and neural crest melanocytes from neuroretina cells[J]. J Biol Chem, 2004, 279(40): 41911-41917. DOI: 10.1074/jbc.M404964200.
14.	Müllner-Eidenböck A, Moser E, Frisch H, et al. Waardenburg syndrome type 2 in a Turkish family: implications for the importance of the pattern of fundus pigmentation[J]. Br J Ophthalmol, 2001, 85(11): 1384-1386. DOI: 10.1136/bjo.85.11.1384.
15.	Forrester JV, Dick AD, McMenamin PG, et al. The eye basic sciences in practice[M]. 4th ed. New York: Elsevier (Singapore) Pte Ltd. , 2016: 80-83.
16.	El-Chemaly S, Young LR. Hermansky-pudlak syndrome[J]. Clin Chest Med, 2016, 37(3): 505-511. DOI: 10.1016/j.ccm.2016.04.012.
17.	Jelena B, Christina L, Eric V, et al. Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10[J]. Am J Med Genet A, 2014, 164A(6): 1512-1519. DOI: 10.1002/ajmg.a.36446.
18.	顾虹. Waardenburg综合征一家系二例[J]. 中华眼底病杂志, 2020, 36(12): 971-972. DOI: 10.3760/cma.j.cn511434-20191018-00335.Gu H. Two cases of Waardenburg syndrome in one family[J]. Chin J Ocul Fundus Dis, 2020, 36(12): 971-972. DOI: 10.3760/cma.j.cn511434-20191018-00335.
19.	Bansal Y, Jain P, Goyal G, et al. Waardenburg syndrome-a case report[J]. Cont Lens Anterior Eye, 2013, 36(1): 49-51. DOI: 10.1016/j.clae.2012.10.083.
20.	Wang HH, Chen HS, Li HB, et al. Identification and functional analysis of a novel mutation in the SOX10 gene associated with Waardenburg syndrome type Ⅳ[J]. Gene, 2014, 538(1): 36-41. DOI: 10.1016/j.gene.2014.01.026.
21.	Touraine RL, Attié-Bitach T, Manceau E, et al. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain[J]. Am J Hum Genet, 2000, 66(5): 1496-1503. DOI: 10.1086/302895.
22.	赵娜, 王晶, 肖涵, 等. 中国人群Waardenburg综合征的临床及基因变异特点分析[J]. 中华医学遗传学杂志, 2020, 37(10): 1186-1190. DOI: 10.3760/cma.j.cn511374-20190610-00288.Zhao N, Wang J, Xiao H, et al. Clinical and genetic characteristics of Chinese patients with Waardenburg syndrome[J]. Chin J Med Genet, 2020, 37(10): 1186-1190. DOI: 10.3760/cma.j.cn511374-20190610-00288.

1. Ahmed Jan N, Mui RK, Masood S. Waardenburg syndrome[M]. StatPearls[Internet]: Treasure Island (FL), 2021. https://www.ncbi.nlm.nih.gov/books/NBK560879/.
2. Newton V. Hearing loss and Waardenburg's syndrome: implications for genetic counselling[J]. J Laryngol Otol, 1990, 104(2): 97-103. DOI: 10.1017/s002221510011196x.
3. Pingault V, Ente D, Dastot-Le Moal F, et al. Review and update of mutations causing Waardenburg syndrome[J]. Hum Mutat, 2010, 31(4): 391-406. DOI: 10.1002/humu.21211.
4. Nicole LD, Chaya K. The neural crest[M]. 2nd ed. London: Cambridge University Press, 1999: 24-27.
5. Read AP, Newton VE. Waardenburg syndrome[J]. J Med Genet, 1997, 34(8): 656-665. DOI: 10.1136/jmg.34.8.656.
6. Bocángel MAP, Melo US, Alves LU, et al. Waardenburg syndrome: novel mutations in a large Brazilian sample[J]. Eur J Med Genet, 2018, 61(6): 348-354. DOI: 10.1016/j.ejmg.2018.01.012.
7. Liu Y, Pan H, Wang J, et al. Ophthalmological features and treatments in five cases of Waardenburg syndrome[J]. Exp Ther Med, 2020, 20(4): 3072-3077. DOI: 10.3892/etm.2020.9035.
8. Tang XJ, Ping XY, Luo CQ, et al. Dystrophia canthorum in Waardenburg syndrome with a novel MITF mutation[J]. Int J Ophthalmol, 2020, 13(7): 1054-1059. DOI: 10.18240/ijo.2020.07.06.
9. Vichare N, Bhargava N. Waardenburg syndrome: a rare case with bilateral congenital cataract: an unusual entity[J]. Med J Armed Forces India, 2013, 69(2): 172-174. DOI: 10.1016/j.mjafi.2012.02.017.
10. Cortés-González V, Zenteno JC, Guzmán-Sánchez M, et al. Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations[J]. Am J Med Genet A, 2016, 170(12): 3294-3297. DOI: 10.1002/ajmg.a.37937.
11. Shields CL, Nickerson SJ, Al-Dahmash S, et al. Waardenburg syndrome: iris and choroidal hypopigmentation[J]. JAMA Ophthalmol, 2013, 131(9): 1167-1173. DOI: 10.1001/jamaophthalmol.2013.4190.
12. Mullaney PB, Parsons MA, Weatherhead RG, et al. Clinical and morphological features of Waardenburg syndrome type Ⅱ[J]. Eye (Lond), 1998, 12 (Pt 3a): 353-357. DOI: 10.1038/eye.1998.85.
13. Planque N, Raposo G, Leconte L, et al. Microphthalmia transcription factor induces both retinal pigmented epithelium and neural crest melanocytes from neuroretina cells[J]. J Biol Chem, 2004, 279(40): 41911-41917. DOI: 10.1074/jbc.M404964200.
14. Müllner-Eidenböck A, Moser E, Frisch H, et al. Waardenburg syndrome type 2 in a Turkish family: implications for the importance of the pattern of fundus pigmentation[J]. Br J Ophthalmol, 2001, 85(11): 1384-1386. DOI: 10.1136/bjo.85.11.1384.
15. Forrester JV, Dick AD, McMenamin PG, et al. The eye basic sciences in practice[M]. 4th ed. New York: Elsevier (Singapore) Pte Ltd. , 2016: 80-83.
16. El-Chemaly S, Young LR. Hermansky-pudlak syndrome[J]. Clin Chest Med, 2016, 37(3): 505-511. DOI: 10.1016/j.ccm.2016.04.012.
17. Jelena B, Christina L, Eric V, et al. Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10[J]. Am J Med Genet A, 2014, 164A(6): 1512-1519. DOI: 10.1002/ajmg.a.36446.
18. 顾虹. Waardenburg综合征一家系二例[J]. 中华眼底病杂志, 2020, 36(12): 971-972. DOI: 10.3760/cma.j.cn511434-20191018-00335.Gu H. Two cases of Waardenburg syndrome in one family[J]. Chin J Ocul Fundus Dis, 2020, 36(12): 971-972. DOI: 10.3760/cma.j.cn511434-20191018-00335.
19. Bansal Y, Jain P, Goyal G, et al. Waardenburg syndrome-a case report[J]. Cont Lens Anterior Eye, 2013, 36(1): 49-51. DOI: 10.1016/j.clae.2012.10.083.
20. Wang HH, Chen HS, Li HB, et al. Identification and functional analysis of a novel mutation in the SOX10 gene associated with Waardenburg syndrome type Ⅳ[J]. Gene, 2014, 538(1): 36-41. DOI: 10.1016/j.gene.2014.01.026.
21. Touraine RL, Attié-Bitach T, Manceau E, et al. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain[J]. Am J Hum Genet, 2000, 66(5): 1496-1503. DOI: 10.1086/302895.
22. 赵娜, 王晶, 肖涵, 等. 中国人群Waardenburg综合征的临床及基因变异特点分析[J]. 中华医学遗传学杂志, 2020, 37(10): 1186-1190. DOI: 10.3760/cma.j.cn511374-20190610-00288.Zhao N, Wang J, Xiao H, et al. Clinical and genetic characteristics of Chinese patients with Waardenburg syndrome[J]. Chin J Med Genet, 2020, 37(10): 1186-1190. DOI: 10.3760/cma.j.cn511374-20190610-00288.

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Chinese Journal of Ocular Fundus Diseases

Analysis of ocular clinical features and gene mutations of Waardenburg syndrome

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