Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33...

Cone-rod dystrophy (CRD) is an inherited retinal dystrophy characterized by decreased visual acuity, color vision defects, and progressive loss of peripheral vision. RAB28-associated CRD is genetically homogeneous and results from pathogenic variants in the RAB28 gene, which is essential for photoreceptor function.

Fundus examinations, optical coherence tomography, color vision tests, and full-field electroretinography (ERG) were performed in the proband. Genetic analysis, including clinical exome sequencing (CES), Sanger sequencing and chromosomal microarray (CMA), was conducted to determine the genetic cause in the proband. The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and thinning of the photoreceptor layers. Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced. Genetic analysis identified that the heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant was inherited exclusively from the father. Additionally, a 3.4 Mb deletion on chromosome 4p16.1p15.33 was detected only in the proband. Four genes associated with Mendelian diseases, including CLNK (OMIM *611434), HS3ST1 (*603244), NKX3-2 (*602183), and RAB28 (*612994), are located within this deletion region.

This case illustrates a rare combination of a heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant and a de novo 4p16.1p15.33 deletion, which is associated with AR CRD. Although extremely rare, bi-allelic RAB28 pathogenic variants can result from one inherited allele and a de novo deletion in the other.