A cone-rod dystrophy patient with a homozygous RP1L1 mutation

Abstract

Purpose: To describe a family with a cone-rod dystrophy (CRD) carrying a homozygous mutation in the RP1-like protein 1 (RP1L1) gene.

Methods: A family including one subject affected with CRD and three unaffected members without evidence of consanguinity underwent detailed ophthalmic and clinical evaluations including high-resolution imaging of retinal morphology by adaptive optics (AO) fundus camera. Mutation screening of the coding sequence of RP1L1 was performed by DNA sequencing analysis. Five computational assessment tools were used to predict the protein function (SIFT, Polyphen2, Align GVGD, PMut). In order to investigate other putative pathogenic variant(s), a next-generation-sequencing (NGS) approach was applied to the CRD patient with an exon sequencing array targeting 121 known genes underlying retinal diseases.

Results: The patient showed a mild reduction of cone and flicker response in full-field electroretinogram (ERG). Her ERG also showed slight decrease in the amplitude of rod responses. Elipsoid and interdigitation zone on spectral-domain optical coherence tomography (SD-OCT) images were severely disturbed. Focal macular ERGs showed a reduced amplitude of the a- and b-wave. Multifocal ERGs (mfERGs) responses were severely reduced. AO images of the patient showed severe reduction of cone density and irregular cone mosaic. A homozygous RP1L1 mutation (c.3628 T>C) was identified in the patient. The mutation c.3628 T>C in exon 4 resulted in the substitution of proline for serine at amino acid position 1210 (p.S1210P). The serine at position 1210 is well conserved among the RP1L1 family in other mammalian species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 460 Japanese control alleles. Family members with heterozygous p.S1210P mutation showed normal best-corrected visual acuity, SD-OCT, mfERGs, focal macular ERGs, and AO analysis. The NGS approach only identified missense changes at the heterozygous state in PCDH15 (p.P923L), RPGRIP1 (p.V1211I), and GPR98 (p.L2422F), which did not co-segregate with the phenotype or /and were predicted to be benign.

Conclusions: We have demonstrated a possibility that autosomal recessive cone-rod dystrophy may be caused by homozygous RP1L1 mutations.

Keywords: 539 genetics • 688 retina • 507 electrophysiology: clinical