A single ancestral allele of the gene TMEM216 is a common cause of recessive retinitis pigmentosa in families of African ethnicity

Abstract

Purpose : A significant proportion of families with Retinitis Pigmentosa (RP) remain molecularly unsolved: the sensitivity of testing is less in those of African ethnicity. Here we present evidence that a single allele of TMEM216, a gene known to cause a severe recessive ciliopathy in childhood, explains a significant proportion of undiagnosed families.

Methods : We analysed WGS data within two large UK cohort studies, NIHR Bioresource for Rare Disease (NIHRRD) and the UK 100,000 genomes project (100KGP), to determine the molecular diagnosis of unsolved patients with retinal dystrophy. SNPs within 1Mb surrounding the candidate variant were genotyped in silico to infer the presence of any ancestral haplotypes and their size. Clinical data were retrieved from affected patients. Other independent cohorts of patients were analysed.

Results : Of 75131 participants of 100KGP, 2316 had retinal dystrophy, 35% labelled as solved. Of the whole cohort there were 48 heterozygotes and 18 homozygotes for a base substitution upstream of TMEM216, namely c.-69G>T (GRCh38 chr11-61392563-G-T). All 18 homozygotes were unsolved RP patients (14 unrelated families).

Of 672 probands with suspected inherited retinal dystrophy in NIHRRD, 249 remained molecularly unsolved. Six unsolved probands were homozygous for the c.-69G>T variant. One further unsolved patient was a mixed heterozygote for this and TMEM216 c.35-2A>G, a likely pathogenic variant.

Of the 25 biallelic patients, clinical data were available on 19 (Moorfields London, age 18-60 years, 11 females). All had night-blindness in the first decade of life, with progressive loss of peripheral field over subsequent decades. Foveal structure and function were initially retained, with loss of acuity from the third decade. OCT, and en face imaging were of typical RP. No evident systemic features suggestive of ciliopathy were noted. All were of Black African or Caribbean ancestry.

All 18 homozygotes within 100KGP shared a common region of homozygosity of 225kb including the neighbouring gene TMEM138. All other shared SNPs within this region had a MAF >0.14.

Conclusions : These data support the hypothesis that homozygosity and mixed heterozygosity for an ancestral allele of TMEM216 (GnomAD African MAF 0.005) cause non-syndromic retinopathy. One testable mechanism is that the variant causes reduced rather than abrogated TMEM216 gene expression.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.