Phenotype Variations Caused by Mutations in the RP1L1 Gene in a Large Mainly German Cohort

Mutations in the retinitis pigmentosa-1-like-1 (RP1L1) gene are the major cause of autosomal dominant occult macular dystrophy (OCMD), while recessive mutations have been linked to autosomal recessive retinitis pigmentosa (arRP). We present the clinical phenotype of a large German OCMD cohort, as well as four RP patients.

A total of 42 OCMD patients (27 families) and 4 arRP patients (3 families) with genetically confirmed mutations in RP1L1 were included. Genomic DNA was analyzed by targeted analysis of the c.133C>T;p.R45W mutation for all RP or macular dystrophy-related genes. All patients underwent ophthalmologic examination including psychophysical tests, electrophysiology, fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT). Follow-up time was up to 12 years.

In 25 OCMD index patients genomic testing revealed the heterozygous mutation c.133C>T;p.R45W in RP1L1; one patient was homozygous for the mutation. Two OCMD patients displayed the variants c.3599G>A;p.G1200D and c.2849G>A;p.R950H, respectively, in a heterozygous state. All OCMD patients showed characteristic clinical findings and typical microstructural photoreceptor changes. Two arRP patients displayed the novel homozygous mutations c.3022C>T;p.Q1008* and c.1107G>A;p.W369*, respectively, while two RP-siblings carried the two heterozygous mutations c.455G>A;p.R152Q and c.5959C>T;p.Q1987*, the first also being novel. All arRP cases were mild with disease onset ≈30 years and preserved ERG-responses.

OCMD phenotype showed consistent clinical findings including classical microstructural changes on SD-OCT. An important hallmark of RP1L1-related OCMD is the dominant family history with reduced penetrance. Furthermore, novel mutations in association with arRP were identified, outlining the complexity of the protein.