A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews.

Purpose: To investigate the genetic basis and clinical manifestations of a characteristic form of retinal degeneration in the Yemenite Jewish population.

Methods: Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic retinal degeneration was performed in a Yemenite Jewish family segregating autosomal recessive severe retinal degeneration. The causative mutation was detected by direct sequencing of the underlying gene, and its prevalence in additional affected and unaffected Yemenite Jews was determined. Patients who were homozygous for this mutation underwent ophthalmic evaluation, including funduscopy, electroretinography, electro-oculography, perimetry, and color vision testing.

Results: In the studied Yemenite Jewish family, we found evidence for linkage to the CERKL gene. Direct sequencing revealed a novel homozygous splice-site mutation, c.238+1G>A. An in vitro splicing assay demonstrated that this mutation leads to incorrect splicing. c.238+1G>A was found to cause retinal degeneration in six additional Yemenite Jewish families. The carrier frequency of this mutation in the Yemenite Jewish population is 4.4%. All c.238+1G>A homozygotes manifest widespread progressive impairment of rod and cone function with early macular involvement.

Conclusions: c.238+1G>A is the second reported mutation of CERKL and is a prevalent founder mutation that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. It is associated with a characteristic retinal degeneration phenotype with early macular involvement, concomitant progression of rod and cone impairment, and characteristic fundus findings. The identification of this mutation and phenotype will facilitate molecular diagnosis, carrier screening, and genetic counseling in the Yemenite Jewish population.