Table 3.
Description of the new pathogenic variants identified in our cohort.
| Phenotype | F | Gene | New pathogenic variant | Phenotypes | Literatures | Hypothesis /note |
|---|---|---|---|---|---|---|
| LCA | F1 | RPGRIP1 | c.3113_3114delCT | visual acuity was limited to light perception | Several studies have shown that patients with RPGRIP1 pathogenic variants have a greater variation in phenotype severity depending on the localization of the variants44 | Most LCA-associated pathogenic variants are located in a segment that encodes two C2 domains45. Some RP- and LCA-causing pathogenic variants in either RHD or RID were shown to impair the interaction between the two46. These data may explain this phenotypic variation in our patient |
| F2 | GUCY2D | c.2660 T > G | severe visual dysfunctions | 70% of families with LCA caused by pathogenic variants in GUCY2D originate from Mediterranean countries47 | This protein is involved in ciliary transport and abnormal trafficking was associated with the most severe visual dysfunctions (LP, NLP at birth)48 which are similar to those described in members of family F2 | |
| F3 | CRB1 | c.3542 + 1G > A | LCA | CRB1-linked pathogenic variants cause specific fundus features: preservation of the para-arteriolar retinal pigment epithelium and retinal telangiectasia with exudation48 but this may not be exclusive | The presence of novel CRB1 pathogenic variants in our cohort expands the mutation spectrum of CRB1 | |
| CRD | F8 | CDHR1 | c.863-2_863-1delAG | CRD | Previous reports showed that the majority of CDHR1 pathogenic variants likely result in nonsense mediated mRNA decay49 | A recent study demonstrated that pathogenic variants in CDHR1 lead both to RP and CD or CRD49. Stingl et al. proposed that an early maculopathy might be a symptom to be expected in all patients with CDHR1-related retinopathy regardless of age49, as found in our patients |
| F9 | C8ORF37 | c.470 + 1G > T | Constant early macular involvement and a variable phenotype depending on the age | Pathogenic variants in C8ORF37 is a rare cause of IRD (0,4% in Pakistani cohort)50 | The phenotype of the patients shows broad variability ranging from CRD to RP with early macular involvement51,52 to syndromic conditions: Bardet-Biedl syndrome (BBS)53 | |
| F11 | ABCA4 | c.1916A > G | CRD | According to several studies there is a frequent ‘ethnic group-specific’ ABCA4 alleles54,55, however, populations outside of Europe are comparatively less well-characterized | The most frequent variant observed in our Tunisian cohort is p.E1087K. Our result needs to be confirmed by analyzing more cases with STGD | |
| RP | F19 | CNGB1 | c.2293C > T | AR-RP | There is a gene-phenotype relationship between CNGB1 and ar-RP56 which is consistent with our results | This expands the spectrum of CNGB1 variants in RP cases |
| CSNB | F26 | TRPM1 | c.3947 T > G | CSNB | More than 35 pathogenic variants in TRPM1 are found in approximately half of all patients with complete congenital stationary night blindness (cCSNB)57 | High myopia has been consistently reported, similarly to the clinical data of our index patient58 |
LCA = Leber congenital amaurosis; CRD = cone rod dystrophy; RP = retinitis pigmentosa; CSNB = congenital stationary night blindness; AR-RP = autosomal recessive retinitis pigmentosa; IRD = Inherited retinal dystrophies; STGD = Stargardt disease; LP = Light perception; NLP = No light perception.