A founder deletion in the TRPM1 gene associated with congenital stationary night blindness and myopia is highly prevalent in Ashkenazi Jews

Yoel Hirsch,Hagit Muallem,Josef Ekstein,David A Zeevi,Byron L Lam,Madhulatha Pantrangi,John (Pei-Wen) Chiang,Sholem Y Scher,Cadina C Cohen,Bitya Cherki,Rachel Bringer,Martin M Johansson

doi:10.1038/s41439-019-0076-4

Abstract

Congenital stationary night blindness (CSNB) is a disease affecting the night vision of individuals. Previous studies identified TRPM1 as a gene involved in reduced night vision. Homozygous deletion of TRPM1 was the cause of CSNB in several children in 6 Ashkenazi Jewish families, thereby prompting further investigation of the carrier status within the families as well as in large cohorts of unrelated Ashkenazi and Sephardi individuals. Affected children were tested with a CSNB next-generation (NextGen) sequencing panel. A deletion of TRPM1 exons 2 through 7 was detected and confirmed by PCR and sequence analysis. A TaqMan-based assay was used to assess the frequency of this deletion in 18266 individuals of Jewish descent. High-throughput amplicon sequencing was performed on 380 samples to determine the putative deletion-flanking founder haplotype. Heterozygous TRPM1 deletions were found in 2.75% (1/36) of Ashkenazi subjects and in 1.22% (1/82) individuals of mixed Ashkenazi/Sephardic origin. The homozygous deletion frequency in our data was 0.03% (1/4025) and was only found in Ashkenazi Jewish individuals. Homozygous deletion of exons 2–7 in TRPM1 is a common cause of CSNB and myopia in many Ashkenazi Jewish patients. This deletion is a founder Ashkenazi Jewish deletion.

Highlights

Congenital stationary night blindness (CSNB) is a disorder of the retina characterized by rod photoreceptor dysfunction or signal transmission defects from photoreceptor to bipolar cells[1]
At age 3, he was diagnosed with myopia, which progressed to −13 diopter bilaterally by age 18 years with the bestcorrected visual acuity of 20/30 in each eye (Table 1)
2 We investigated another Ashkenazi Jewish family of Hungarian descent related to Family 1, with one child exhibiting CSNB symptoms by using the PCR and Sanger sequencing methods as described above

Summary

Introduction

Congenital stationary night blindness (CSNB) is a disorder of the retina characterized by rod photoreceptor dysfunction or signal transmission defects from photoreceptor to bipolar cells[1]. A recent observation of CSNB in Appaloosa horses, which exhibited reduced vision in dim light conditions, was linked to significantly reduced expression levels of TRPM1 mRNA in the retina[6]. TRPM1 homozygous deletion comprising exons [2,3,4,5,6,7] has been previously described in a female patient with complete congenital stationary night blindness (cCSNB)[7]. A carrier frequency of 2.1% (1 in 50) for TRPM1 exon [2,3,4,5,6,7] deletion has been reported by Chiang et al in the Ashkenazi Jewish population in an initial screening and PCR method development study[8].

Methods

Results

Conclusion