Abstract
The specific association of Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (LCA-like) with sensorineural hearing loss (SHL) is uncommon. Recently, we ascribed some of these distinctive associations to dominant and de novo mutations in the β-tubulin 4B isotype-encoding gene (TUBB4B), providing a link between a sensorineural disease and anomalies in microtubules behavior. Here, we report 12 sporadic cases with LCA/SHL or LCA-like/SHL and no TUBB4B mutation. Trio-based whole exome sequencing (WES) identified disease-causing mutations in 5/12 cases. Four out of five carried biallelic mutations in PEX1 (1/4) or PEX6 (3/4), involved in peroxisome biogenesis disorders from Zellweger syndrome characterized by severe neurologic and neurosensory dysfunctions, craniofacial abnormalities, and liver dysfunction to Heimler syndrome associating SHL, enamel hypoplasia of the secondary dentition, nail abnormalities, and occasional retinal disease. Upon reexamination, the index case carrying PEX1 mutations, a 4-year-old girl, presented additional symptoms consistent with Zellweger syndrome. Reexamination of individuals with PEX6 mutations (1/3 unavailable) revealed normal nails but enamel hypoplasia affecting one primary teeth in a 4-year-old girl and severe enamel hypoplasia of primary teeth hidden by dental prosthesis in a 50-year-old male, describing a novel PEX6-associated disease of the Zellweger/Heimler spectrum. Finally, hemizygosity for a CACNA1F mutation was identified in an 18-year-old male addressed for LCA/SHL, redirecting the retinal diagnosis to congenital stationary night blindness (CSNB2A). Consistent with the pure CSNB2A retinal involvement, SHL was ascribed to biallelic mutations in another gene, STRC, involved in nonprogressive DFNB16 deafness.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Baumann L, Gerstner A, Zong X et al (2004) Functional characterization of the L-type Ca(2+) channel Cav1.4-alpha-1 from the mouse retina. Invest Ophthal Vis Sci 45(2):708–713
Gerber S, Alzayady KJ, Burglen L et al (2016) Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome. Am J Hum Genet 98(5):971–980
Kaplan J (2008) Leber congenital amaurosis: from darkness to spotlight. Ophthalmic Genet 29(3):92–98
Mechaussier S, Luscan R, Paul A et al (2017) Mutations in TUBB4B cause a distinctive sensorineural disease. Am J Hum Genet 101(6):1006–1012
Men CJ, Bujakowska KM, Comander J et al (2017) The importance of genetic testing as demonstrated by two cases of CACNA1F-associated retinal generation misdiagnosed as LCA. Mol Vis 23:695–706
Michelakakis HM, Zafeiriou DI, Moraitou MS et al (2004) PEX1 deficiency presenting as Leber congenital amaurosis. Pediatr Neurol 31(2):146–149
Minegishi Y, Sheng X, Yoshitake K et al (2016) CCT2 mutations evoke Leber congenital amaurosis due to chaperone complex instability. Sci Rep 6:33742
Minegishi Y, Nakaya N, Tomarev SI (2018) Mutation in the zebrafish cct2 gene leads to abnormalities of cell cycle and cell death in the retina: a model of CCT2-related Leber congenital amaurosis. Invest Ophthalmol Vis Sci 59(2):995–1004
Ratbi I, Falkenberg KD, Sommen M et al (2015) Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am J Hum Genet 97(4):535–545
Rozet JM, Gérard X (2015) Understanding disease pleiotropy: from puzzle to solution. Sci Transl Med 7(291):291fs24
Smith CE, Poulter JA, Levin AV et al (2016) Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet 24(11):1565–1571
Tian G, Cowan NJ (2013) Tubulin-specific chaperones: components of a molecular machine that assembles the α/β heterodimer. Methods Cell Biol 115:155–171
Verpy E, Masmoudi S, Zwaenepoel I et al (2001) Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus. Nature Genet 29(3):345–349
Waterham HR, Ebberink MS (2012) Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta 1822(9):1430–1441
Waters AM, Beales PL (2011) Ciliopathies: an expanding disease spectrum. Pediatr Nephrol 26(7):1039–1056
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this paper
Cite this paper
Mechaussier, S., Marlin, S., Kaplan, J., Rozet, JM., Perrault, I. (2019). Genetic Deciphering of Early-Onset and Severe Retinal Dystrophy Associated with Sensorineural Hearing Loss. In: Bowes Rickman, C., Grimm, C., Anderson, R., Ash, J., LaVail, M., Hollyfield, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1185. Springer, Cham. https://doi.org/10.1007/978-3-030-27378-1_38
Download citation
DOI: https://doi.org/10.1007/978-3-030-27378-1_38
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-27377-4
Online ISBN: 978-3-030-27378-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)