De‐novo “germline second hit” loss‐of‐heterozygosity RBP3 deletion mutation causing recessive high myopia

Abstract

AbstractKnudson's “two hit” hypothesis, mostly associated with cancer, relates to a primary heterozygous germline mutation complemented by a somatic mutation in the second allele. When the somatic “second hit” is a deletion mutation, the heterozygosity due to the first hit is lost (“loss of heterozygosity”). As the rate of germline mutations is almost two orders of magnitude lower than that of somatic mutations, de‐novo germline mutations causing autosomal recessive diseases in carriers of inherited heterozygous mutations are not common. We delineate a case of high myopia presenting at infancy with mild diminution of retinal responses. Exome sequencing identified a paternally inherited apparently homozygous missense mutation in RBP3. Chromosomal microarrays delineated a de‐novo germline heterozygous deletion encompassing RBP3, verified through revision of WES data. Thus, we demonstrate an inherited RBP3 missense mutation complemented by a de‐novo germline RBP3 deletion, causing loss of heterozygosity of the inherited mutation. We describe a novel RBP3 missense mutation, report the first isolated RBP3 deletion, and demonstrate infantile high myopia as an initial presentation of RBP3 disease. Notably, we highlight de‐novo germline deletion mutations causing “loss of heterozygosity” of inherited heterozygous mutations, culminating in autosomal recessive diseases, and discuss the scarce literature.