CRB1 Gene Mutation Causing Different Phenotypes of Leber Congenital Amaurosis in Siblings


Purpose: We report a rare case of CRB1 gene mutation in two siblings (sisters) affected with the exact same genetic mutation on both CRB1 genes resulting in varying phenotypes.

Case Report: CRB1 gene mutation in this case has resulted in causing varying degrees of Leber congenital amaurosis (LCA) in both sisters with a more severe phenotype in the older sibling causing LCA-8 with retinitis pigmentosa spectrum in both eyes and a milder phenotype causing LCA-8 with less severe rod cone dystrophy in the younger sister.

Conclusion: In summary, the mechanisms of varying phenotypes resulting from CRB1 genetic mutation are still not well understood. We concluded that the presence of different phenotypes associated with identical genotypic mutation of a single gene in siblings or in a family is important especially when dealing with retinal dystrophies.


CRB1, LCA, Retinitis Pigmentosa, Rod cone Dystrophy

1. Hasan S, Azmeh A, Mostafa O, Megarbane A. Coat’s like vasculopathy in leber congenital amaurosis secondary to homozygous mutations in CRB1: a case report and discussion of the management options. BMC Res Notes 2016;9:91.

2. McKusick V [Internet]. OMIM Entry - # 204000 - Leber Congenital Amaurosis 1; LCA1.; 1986 [updated 2019 Aug 28]. Available from:

3. Weleber RG, Francis PJ, Trzupek KM, Beattie C. Leber Congenital Amaurosis. 2004 [Updated 2013 May 2]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al, editors. Gene Reviews [Internet]. Seattle (WA): University of Washington, Seattle;1993– 2018. Available from: NBK1298/.

4. den Hollander AI, Ghiani M, de Kok YJ, Wijnholds J, Ballabio A, Cremers FP, et al. Isolation of CRB1, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech Dev 2002;110:203–207.

5. Richard M, Roepman R, Aartsen WM, van Rossum AG, den Hollander AI, Knust E, et al. Towards understanding CRUMBS function in retinal dystrophies. Hum Mol Genet 2006;15:235–243.

6. Pocha SM, Knust E. Complexities of Crumbs function and regulation in tissue morphogenesis. Curr Biol 2013;23:289–293.

7. Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat 2004;23:306–317.

8. Simonelli F, Ziviello C, Testa F, Rossi S, Fazzi E, Bianchi PE, et al. Clinical and molecular genetics of Leber’s congenital amaurosis: a multicenter study of Italian patients. Invest Ophthalmol Vis Sci 2007;48:4284–4290.

9. den Hollander A, ten Brink JB, de Kok YJ, van Soest S, van dem Born L, van Driel MA, et al. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet 1999;23:217–221.

10. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358:2240–2248.

11. Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Benicelli JL, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010;18:643–650.

12. Ehrenberg M, Pierce EA, Cox GF, Fulton AB. CRB1: one gene, many phenotypes. Semin Ophthalmol 2013;28:397–405.

13. Bujakowska K, Audo I, Mohand-Said S, Lancelot ME, Antoio A, Germain A, et al. CRB1 mutations in inherited retinal dystrophies. Hum Mutat 2012;33:306–315.

14. Jonsson F, Burstedt MS, Sandgren O, Norberg A, Golovleva I. Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family. Eur J Hum Genet 2013;21:1266–1271.

15. Li S, Shen T, Xiao X, Guo X, Zhang Q. Detection of CRB1 mutations in families with retinal dystrophy through phenotype-oriented mutational screening. Int J Mol Med 2014;33:913–918.