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Riccardo Sangermano, Susanne Roosing, L Ingeborgh Van Den Born, Carel C B Hoyng, Frans Cremers, Lonneke Haer-Wigman; Recurrence of identical combinations of mutations in MFSD8 or POC1B in persons with cone dysfunctions due to founder effects and putative functional constraints. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2895.
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© ARVO (1962-2015); The Authors (2016-present)
We previously identified MFSD8 or POC1B compound heterozygous variants in non-syndromic cone dystrophy (CD) cases. Both genes are implicated in syndromic phenotypes: MFSD8 in Batten disease and the POC1B ortholog poc1b in a syndromic zebrafish ciliopathy. This suggest that non-syndromic CD patients carrying MSFD8 or POC1B variants have residual activity of the respective proteins, due to the hypomorphic character of the identified variants. In order to establish genotype-phenotype correlation models we searched for additional non-syndromic CD cases harboring mutations in MFSD8 or POC1B.
Whole exome sequencing (WES) was performed in 30 Dutch CD probands and Sanger sequencing was used for segregation analysis. An extensive clinical examination was conducted for persons harboring MFSD8 or POC1B variants. Haplotype analyses were performed using single nucleotide polymorphisms (SNPs) identified in WES data and selective SNP genotyping. Sequencing of MFSD8 exons 11 and 12 was performed in 235 retinal dystrophy probands and 300 controls.
For MFSD8, WES identified a Dutch CD case carrying compound heterozygous variants (p.K333Kfs*3; p.E336Q) described in another CD case (Roosing et al., Ophthalmology, 2014). Similarly, POC1B compound heterozygous variants (c.810+1G>T; p.Q67del) were identified in two unrelated CD cases (Roosing et al., Am J Hum Genet., 2014). For both genes, the affected cases carried identical haplotypes encompassing a region of ~ 2.8 or 1.5 Mb respectively. Besides, the MFSD8 p.E336Q variant was found in combination with p.E381* in five siblings with CD and in a heterozygous state in 1/300 Dutch controls and in 5/235 CD cases.
We determined shared haplotypes in two Dutch cases with the same MFSD8 compound variants and in two cases with the same POC1B compound heterozygous variants, suggesting the presence of founder alleles for these genes. The MFSD8 p.E336Q mutation was found in all three CD families but not in 35 Batten disease probands reported earlier, indicating that it is a hypomorphic variant. Interestingly, all MFSD8 variants found in non-syndromic CD cases are located in the last three exons, which are jointly present or absent in MFSD8 isoforms. These findings suggest that both functional constraints and founder effects of mutations led to the recurrence of these genetic variants.
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