Table 3 Description of the new pathogenic variants identified in our cohort.

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 involvement^51,52 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 alleles^54,55, 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