The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

Disruption of the basal body protein POC1B results in autosomal-recessive cone-rod dystrophy

Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.G1n67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.G1n67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.G1n67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors

Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia

PURPOSE: To identify the genetic defect in two Pakistani families with autosomal recessive achromatopsia. METHODS: Two families (RP26 and RP44) were originally diagnosed with retinal dystrophy based upon their medical history. To localize the causative genes in these families, homozygosity mapping was performed using Affymetrix 10K single nucleotide polymorphism (SNP) arrays. Sequence analysis was used to find the mutations in candidate genes cyclic nucleotide-gated channel alpha-3 (CNGA3; family RP26) and cyclic nucleotide-gated channel beta-3 (CNGB3; family RP44). Control individuals were analyzed by allele-specific PCR for the CNGA3 mutation and BstXI restriction analysis for the CNGB3 mutation. After genetic analysis, clinical diagnosis was re-evaluated by electroretinography and color vision testing. During the course of this study, selected affected members of family RP26 were given pink glasses as supportive therapy. RESULTS: Sequence analysis of the positional candidate genes identified a novel missense mutation in CNGA3 (c.822G>T; p.R274S) in family RP26, and a novel CNGB3 frameshift mutation (c.1825delG; p.V609WfsX9) in family RP44. Clinical re-evaluation after genetic analysis revealed that both families have segregating autosomal recessive achromatopsia. CONCLUSIONS: Genetic analysis of two Pakistani families with retinal disease enabled the establishment of the correct diagnosis of achromatopsia. Two novel mutations were identified in CNGA3 and CNGB3 that are both specifically expressed in cone photoreceptors. Re-evaluation of the clinical status revealed that both families had achromatopsia. The use of pink glasses in patients was helpful in reducing photophobia and enabled rod-mediated vision

Identification of splice defects due to noncanonical splice site or deep‐intronic variants in ABCA4

Pathogenic variants in the ATP-binding cassette transporter A4 (ABCA4) gene cause a continuum of retinal disease phenotypes, including Stargardt disease. Noncanonical splice site (NCSS) and deep-intronic variants constitute a large fraction of disease-causing alleles, defining the functional consequences of which remains a challenge. We aimed to determine the effect on splicing of nine previously reported or unpublished NCSS variants, one near exon splice variant and nine deep-intronic variants in ABCA4, using in vitro splice assays in human embryonic kidney 293T cells. Reverse transcription-polymerase chain reaction and Sanger sequence analysis revealed splicing defects for 12 out of 19 variants. Four deep-intronic variants create pseudoexons or elongate the upstream exon. Furthermore, eight NCSS variants cause a partial deletion or skipping of one or more exons in messenger RNAs. Among the 12 variants, nine lead to premature stop codons and predicted truncated ABCA4 proteins. At least two deep-intronic variants affect splice enhancer and silencer motifs and, therefore, these conserved sequences should be carefully evaluated when predicting the outcome of NCSS and deep-intronic variants

The common ABCA4 variant p.Asn1868ile shows nonpenetrance and variable expression of stargardt disease when present in trans with severe variants

PURPOSE. To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. METHODS. The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospe

The attenuated end of the phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to a non-neuronopathic phenotype

BACKGROUND: The phenotypic spectrum of many rare disorders is much wider than previously considered. Mucopolysaccharidosis type III (Sanfilippo syndrome, MPS III), is a lysosomal storage disorder traditionally considered to be characterized by childhood onset, progressive neurocognitive deterioration with a rapidly or slowly progressing phenotype. The presented MPS III case series demonstrates adult onset phenotypes with mild cognitive impairment or non-neuronopathic phenotypes. METHODS: In this case series all adult MPS III patients with a mild- or non-neuronopathic phenotype, who attend the outpatient clinic of 3 expert centers for lysosomal storage disorders were included. A mild- or non-neuronopathic phenotype was defined as having completed regular secondary education and attaining a level of independency during adulthood, involving either independent living or a paid job. RESULTS: Twelve patients from six families, with a median age at diagnosis of 43 years (range 3-68) were included (11 MPS IIIA, 1 MPS IIIB). In the four index patients symptoms which led to diagnostic studies (whole exome sequencing and metabolomics) resulting in the diagnosis of MPS III; two patients presented with retinal dystrophy, one with hypertrophic cardiomyopathy and one with neurocognitive decline. The other eight patients were diagnosed by family screening. At a median age of 47 years (range 19-74) 9 out of the 12 patients had normal cognitive functions. Nine patients had retinal dystrophy and 8 patients hypertrophic cardiomyopathy. CONCLUSION: We show the very mild end of the phenotypic spectrum of MPS III, ranging from late-onset stable neurocognitive impairment to a fully non-neuronopathic phenotype. Awareness of this phenotype could lead to timely diagnosis and genetic counseling

Disruption of the Basal Body Protein POC1B Results in Autosomal-Recessive Cone-Rod Dystrophy

Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.Gln67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.Gln67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.Gln67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors