Detection and analysis of gene mutation in a case of child’s renal coloboma syndrome_Chinese Journal of Ocular Fundus Diseases

Authors：

Bai Zhouxian , Jiao Zhihui ,  Kong Xiangdong

Genetic and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China;

Corresponding author：

Kong Xiangdong, Email: kongxd@263.net

Keywords：

Coloboma; Renal insufficiency; PAX2 gene; Frameshift mutation

DOI：

10.3760/cma.j.issn.1005-1015.2018.06.006

Video：

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ObjectiveTo analyze and identify the pathogenic mutation that caused a case of child’s renal coloboma syndrome (RCS).MethodsA child with congenital cataract in the right eye and optic disc defect in the left eye and his parents with normal phenotype were included in the study. The blood of the child and his parents were captured to extract DNA and make molecular test. The possible variants were screened through NGS sequencing using the ophthalmology gene panel on illumina NextSeq 500 platform, and proved the selected PAX2 mutation by Sanger sequencing. Pathogenicity report was retrieved through PubMed and related database. Pathogenicity analysis of the candidate mutated site has careful consideration of the patient’s clinical presentations and sequencing result base on Standards and Guidelines for the Interpretation of Sequence Variants revised by ACMG. According to the results of gene diagnosis, the child was executed related clinical examinations on kidney.ResultsThe sequence result showed that a heterozygous mutation in PAX2, c.70dupG (p.V26Gfs*28), which lead to truncated protein product that terminated after 28 amino acids of the mutated site. Both of his normal parents were not carriers of the heterozygous mutation. Sanger sequencing results of the child and his parents were consistent with the NGS sequencing. The autosomal dominant disease phenotype was inferred to be caused by the heterozygous mutation of c.70dupG (p.V26Gfs*28) of PAX2 gene. Renal color Doppler ultrasound results showed the child with small renal cysts on the left and mildly separated collecting system. Renal function tests showed the child with α1 microglobulin index increased.ConclusionThe heterozygous mutation c.70dupG (p.V26Gfs*28) in PAX2 is the genetic pathogenic cause for the patient with RCS.

Citation： Bai Zhouxian, Jiao Zhihui, Kong Xiangdong. Detection and analysis of gene mutation in a case of child’s renal coloboma syndrome. Chinese Journal of Ocular Fundus Diseases, 2018, 34(6): 552-555. doi: 10.3760/cma.j.issn.1005-1015.2018.06.006 Copy

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8.	Sanyanusin P, Schimmenti LA, McNoe LA, et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux[J]. Nat Genet, 1995, 9(4): 358-364. DOI: 10.1038/ng0495-358.
9.	Thomas R, Sanna-Cherchi S, Warady BA, et al. HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort[J]. Pediatr Nephrol, 2011, 26(6): 897-903. DOI: 10.1007/s00467-011-1826-9.
10.	Cunliffe HE, McNoe LA, Ward TA, et al. The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies[J]. J Med Genet, 1998, 35(10): 806-812.
11.	Bower M, Salomon R, Allanson J, et al. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database[J]. Hum Mutat, 2012, 33(3): 457-466. DOI: 10.1002/humu.22020.
12.	Amiel J, Audollent S, Joly D, et al. PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism[J]. Eur J Hum Genet, 2000, 8(11): 820-826. DOI: 10.1038/sj.ejhg.5200539.
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14.	Iatropoulos P, Daina E, Mele C, et al. Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation[J]. Pediatr Nephrol, 2012, 27(10): 1989-1993. DOI: 10.1007/s00467-012-2205-x.
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1. Schimmenti LA. Renal coloboma syndrome[J]. Eur J Hum Genet, 2011, 19(12): 1207-1212. DOI: 10.1038/ejhg.2011.102.
2. Harasymowycz P, Chevrette L, Decarie JC, et al. Morning glory syndrome: clinical, computerized tomographic, and ultrasonographic findings[J]. J Pediatr Ophthalmol Strabismus, 2005, 42(5): 290-295.
3. Negrisolo S, Benetti E, Centi S, et al. PAX2 gene mutations in pediatric and young adult transplant recipients: kidney and urinary tract malformations without ocular anomalies[J]. Clin Genet, 2011, 80(6): 581-585. DOI: 10.1111/j.1399-0004.2010.01588.x.
4. 彭婕, 张琦, 费萍等. 儿童牵牛花综合征患眼荧光素眼底血管造影特征[J]. 中华眼底病杂志, 2015, 31(4): 355-358. DOI: 10.3760/cma.j.issn.1005-1015.2015.04.011.Peng J, Zhang Q, Fei P, et al. Fundus fluorescein angiography of pediatric morning glory syndrome patients[J]. Chin J Ocul Fundus Dis, 2015, 31(4): 355-358. DOI: 10.3760/cma.j.issn.1005-1015.2015.04.011.
5. 费萍, 张琦, 许宇等. 儿童牵牛花综合征并发视网膜脱离的临床特征及治疗效果观察[J]. 中华眼底病杂志, 2014, 30(1): 46-49. DOI: 10.3760/cma.j.issn.1005-1015.2014.01.012.Fei P, Zhang Q, Xu Y, et al. Clinical analysis and management of pediatric retinal detachment associated with morning glory syndrome[J]. Chin J Ocul Fundus Dis, 2014, 30(1): 46-49. DOI: 10.3760/cma.j.issn.1005-1015.2014.01.012.
6. 王秋菊, 沈亦平, 邬玲仟, 等. 遗传变异分类标准与指南[J]. 中国科学: 生命科学, 2017, 47(6): 668. DOI: 10.1360/N052017-00099.Wang QJ, Shen YP, Wu LQ, et al. Standards and guidelines for the interpretation of sequence variants[J]. Sci Sin Vitae, 2017, 47(6): 668. DOI: 10.1360/N052017-00099.
7. Richards S, Aziz N, Bale S, et al. 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 Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
8. Sanyanusin P, Schimmenti LA, McNoe LA, et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux[J]. Nat Genet, 1995, 9(4): 358-364. DOI: 10.1038/ng0495-358.
9. Thomas R, Sanna-Cherchi S, Warady BA, et al. HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort[J]. Pediatr Nephrol, 2011, 26(6): 897-903. DOI: 10.1007/s00467-011-1826-9.
10. Cunliffe HE, McNoe LA, Ward TA, et al. The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies[J]. J Med Genet, 1998, 35(10): 806-812.
11. Bower M, Salomon R, Allanson J, et al. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database[J]. Hum Mutat, 2012, 33(3): 457-466. DOI: 10.1002/humu.22020.
12. Amiel J, Audollent S, Joly D, et al. PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism[J]. Eur J Hum Genet, 2000, 8(11): 820-826. DOI: 10.1038/sj.ejhg.5200539.
13. Schimmenti LA, Shim HH, Wirtschafter JD, et al. Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome[J]. Hum Mutat, 1999, 14(5): 369-376.
14. Iatropoulos P, Daina E, Mele C, et al. Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation[J]. Pediatr Nephrol, 2012, 27(10): 1989-1993. DOI: 10.1007/s00467-012-2205-x.
15. Rieger G. On the clinical picture of Handmann's anomaly of the optic nerve Morning glory syndrome?[J]. Klin Monbl Augenheilkd, 1977, 170(5): 697-706.

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Detection and analysis of gene mutation in a case of child’s renal coloboma syndrome

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