Bi-Allelic Pathogenic Variations in MERTK Including Deletions Are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa

Abstract

Bi-allelic pathogenic variants in MERTK cause retinitis pigmentosa (RP). Since deletions of more than one exon have been reported repeatedly for MERTK, CNV (copy number variation) analysis of next-generation sequencing (NGS) data has proven important in molecular genetic diagnostics of MERTK. CNV analysis was performed on NGS data of 677 individuals with inherited retinal diseases (IRD) and confirmed by quantitative RT-PCR analysis. Clinical evaluation was based on retrospective records. Clinical re-examination included visual field examination, dark adaption, scotopic and photopic full-field electroretinograms (ffERG), multifocal ERG (mfERG) and optic coherence tomography (OCT). Fourteen variants were detected in MERTK in six individuals, three of which were deletions of more than one exon. Clinical examinations of five out of six individuals revealed a severe phenotype with early-onset generalized retinal dystrophy with night blindness and progressive visual field loss; however, one individual had a milder phenotype. Three individuals had hearing impairments. We show that deletions represent a substantial part of the causative variants in MERTK and emphasize that CNV analysis should be included in the molecular genetic diagnostics of IRDs.

Challenges and Opportunities in the Genetic Analysis of Inherited Retinal Dystrophies in Africa, a Literature Review

“…In retinitis pigmentosa, the implicated genes that appeared across multiple studies include MERTK , PDE6B , CERKL , and ABCA4 [ 14 , 15 ]. MERTK is important in molecular genetics diagnostics because bi-allelic pathogenic variants in MERTK have been linked to RP [ 27 ]. Missense and nonsense variants can occur in MERTK [ 28 ].…”

Systemic taurine treatment affords functional and morphological neuroprotection of photoreceptors and restores retinal pigment epithelium function in RCS rats

“…These rats suffer an impairment of the phagocytic capacity of the retinal pigment epithelium [ [40] , [41] , [42] , [43] ] due to an autosomal recessive mutation in the MERTK gene [ 44 ]. This mutation has also been observed in human patients with a form of early-onset RP [ [45] , [46] , [47] ]. In RCS rats, it causes progressive photoreceptor degeneration [ [2] , [48] , [49] , [50] , [51] , [52] ], increased retinal gliosis [ 50 ] and alteration of the retrograde axonal transport in retinal ganglion cells and retinal ganglion cell loss [ 1 , 2 , 4 , 53 ].…”

Challenges and Opportunities in the Genetic Analysis of Inherited Retinal Dystrophies in Africa, A Literature Review

“…In retinitis pigmentosa, the implicated genes that appeared across multiple studies include MERTK, PDE6B, CERKL, and ABCA4 [14,15]. MERTK is important in molecular genetics diagnostics since bi-allelic pathogenic variants in MERTK have been linked to RP [27]. Missense and nonsense variants can occur in MERTK [28].…”

“…Multiple causative variants can occur in MERTK, some resulting from deletions [27]. Copy number variations (CNVs) in MERTK should be included in genetics studies of RP among Africans to capture the diverse mutations that can cause the disease [27]. The PDE6B gene can undergo missense and putative slicing defects mutations to cause RP [29].…”