Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases

Significance By computing genotype data from six major world populations, we aimed at calculating how many individuals are affected with an autosomal recessive (AR) form of inherited retinal disease (IRD) or carry a mutation that can be transmitted to future generations. By analyzing variants in 187 IRD-associated genes, we detected 10,044 mutations and estimated that 2.7 billion individuals worldwide are carriers of an IRD disease-causing mutation, whereas 5.5 million are expected to be affected. This study will assist clinicians in their decision about the need to perform relevant genetic tests when diagnosing patients with IRDs. Similar studies can take advantage of our approach to calculate the expected number of affected or carrier individuals for any genetic disease with known molecular etiology. One of the major questions in human genetics is what percentage of individuals in the general population carry a disease-causing mutation. Based on publicly available information on genotypes from six main world populations, we created a database including data on 276,921 sequence variants, present within 187 genes associated with autosomal recessive (AR) inherited retinal diseases (IRDs). Assessment of these variants revealed that 10,044 were categorized as disease-causing mutations. We developed an algorithm to compute the gene-specific prevalence of disease, as well as the mutational burden in healthy subjects. We found that the genetic prevalence of AR-IRDs corresponds approximately to 1 case in 1,380 individuals, with 5.5 million people expected to be affected worldwide. In addition, we calculated that unaffected carriers of mutations are numerous, ranging from 1 in 2.26 individuals in Europeans to 1 in 3.50 individuals in the Finnish population. Our analysis indicates that about 2.7 billion people worldwide (36% of the population) are healthy carriers of at least one mutation that can cause AR-IRD, a value that is probably the highest across any group of Mendelian conditions in humans.

[1]  J. J. McAnany,et al.  CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION. , 2019, Retina.

[2]  H. Hakonarson,et al.  Application of ACMG criteria to classify variants in the human gene mutation database , 2019, Journal of Human Genetics.

[3]  Min Goo Lee,et al.  Systematic evaluation of gene variants linked to hearing loss based on allele frequency threshold and filtering allele frequency , 2019, Scientific Reports.

[4]  Ryan L. Collins,et al.  Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes , 2019, bioRxiv.

[5]  Henrique Ferreira,et al.  Design of Antibacterial Agents: Alkyl Dihydroxybenzoates against Xanthomonas citri subsp. citri , 2018, International journal of molecular sciences.

[6]  J. Sahel,et al.  Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort , 2018, International journal of molecular sciences.

[7]  Jörg Hakenberg,et al.  Predicting the clinical impact of human mutation with deep neural networks , 2018, Nature Genetics.

[8]  P. Gouras,et al.  Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes , 2018, Cold Spring Harbor molecular case studies.

[9]  D. Sharon,et al.  Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population , 2018, European Journal of Human Genetics.

[10]  Asan,et al.  Systematic evaluation of a targeted gene capture sequencing panel for molecular diagnosis of retinitis pigmentosa , 2018, PloS one.

[11]  Cristina Has,et al.  Faculty of 1000 evaluation for Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. , 2018 .

[12]  J. Soll,et al.  Plant Mitochondrial Inner Membrane Protein Insertion , 2018, International journal of molecular sciences.

[13]  Adam P. DeLuca,et al.  Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. , 2017, Ophthalmology.

[14]  S. Tsang,et al.  Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration , 2017, Journal of Medical Genetics.

[15]  F. Cremers,et al.  In Silico Functional Meta‐Analysis of 5,962 ABCA4 Variants in 3,928 Retinal Dystrophy Cases , 2017, Human mutation.

[16]  C. Layton,et al.  A Novel ABCA4 Mutation Associated with a Late-Onset Stargardt Disease Phenotype: A Hypomorphic Allele? , 2017, Case Reports in Ophthalmology.

[17]  Dorothy A. Thompson,et al.  Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. , 2017, American journal of human genetics.

[18]  F. Grassmann,et al.  Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort—Impact of Selected Deep Intronic Variants and Common SNPs , 2017, Investigative ophthalmology & visual science.

[19]  I. Chowers,et al.  Whole Exome Sequencing Reveals Mutations in Known Retinal Disease Genes in 33 out of 68 Israeli Families with Inherited Retinopathies , 2015, Scientific Reports.

[20]  H. Rehm,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[21]  Seema M Jamal,et al.  Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. , 2014, American journal of human genetics.

[22]  D. Sharon,et al.  Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations , 2015, Molecular vision.

[23]  R. Allikmets,et al.  Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families. , 2013, Ophthalmology.

[24]  C. Rivolta,et al.  Genes Associated with Retinitis Pigmentosa and Allied Diseases Are Frequently Mutated in the General Population , 2012, PloS one.

[25]  Hanan Hamamy,et al.  Consanguineous marriages , 2011, Journal of Community Genetics.

[26]  A. D. den Hollander,et al.  Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies. , 2010, The Journal of clinical investigation.

[27]  Carlo Rivolta,et al.  Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. , 2002, Human molecular genetics.

[28]  Marianne Haim,et al.  Epidemiology of retinitis pigmentosa in Denmark. , 2002, Acta ophthalmologica Scandinavica. Supplement.

[29]  C. Rivolta,et al.  Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. , 2000, American journal of human genetics.

[30]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[31]  S. Crews,et al.  A study of retinitis pigmentosa in the City of Birmingham. II Clinical and genetic heterogeneity. , 1984, Journal of medical genetics.

[32]  E. Berson,et al.  Prevalence of retinitis pigmentosa in Maine. , 1984, American journal of ophthalmology.

[33]  J. Boughman,et al.  Population genetic studies of retinitis pigmentosa. , 1980, American journal of human genetics.

[34]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.