Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population

Hanany, Mor; Allon, Gilad; Kimchi, Adva; Blumenfeld, Anat; Newman, Hadas; Pras, Eran; Wormser, Ohad; Birk, Ohad S.; Gradstein, Libe; Banin, Eyal; Ben-Yosef, Tamar; Sharon, Dror

doi:10.1038/s41431-018-0152-0

Cited by 19 publications

(10 citation statements)

References 27 publications

(31 reference statements)

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“…In most of these families, the single identified allele is probably causative, and the second allele has been missed due to technical reasons (lack of coverage, inaccurate annotation, nonexonic localization, inability to pick up the genetic defect, or inaccurate interpretation). However, it should be noted that some IRD causative mutations have a very high carrier frequency in the Israeli population, and therefore, IRD patients may be coincidental carriers of these mutations, in addition to the mutations which are actually causing their disease (Hanany et al, ). It is therefore not surprising that in 6% (79/1,368) of solved families, we identified a heterozygous disease‐causing mutation in another IRD gene.…”

Section: Discussionmentioning

confidence: 99%

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A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

et al. 2019

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Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone–rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.

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Section: Discussionmentioning

confidence: 99%

“…Such mutations are frequent among affected individuals from the same ethnic group. The Arab population is characterized by a high rate of consanguinity, leading to increased homozygosity of rare mutant alleles in specific families and villages (Hanany et al, ; Zlotogora, ).…”

Section: Introductionmentioning

confidence: 99%

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

et al. 2019

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“…Further, the involvement of ZNF513 and INPP5E in IRD is reported only in Pakistani and European populations respectively [134]. Population specific founder mutations have also been reported [135]. Our previous studies on Pakistani population identified p.Pro363Thr variant in RPE65 that is specific to the South Asian population as the common causative mutation [7,92].…”

Section: Plos Geneticsmentioning

confidence: 99%

Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis

Biswas

Villanueva²,

Soto‐Hermida

et al. 2021

PLoS Genet

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Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 62 pedigrees (58%), including 41 novel and 53 reported variants in IRD genes. For 58 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In eight pedigrees (13%) we observed atypical causal variants, i.e. unexpected genotype(s), including 5 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 21% of cases. Among the novel mutations, 75% were detected in Mexican and 53% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 48% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.

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“…For CF and pGP analysis, only heterozygous PLPV (not homozygous PLPV) was considered [14][15][16]. Therefore, the allele frequency of heterozygous PLPV (AF V ) and CF V for a variant V were calculated as follows:…”

Section: Carrier Frequency (Cf) and Predicted Genetic Prevalence Analysis (Pgp)mentioning

confidence: 99%

Analysis of Worldwide Carrier Frequency and Predicted Genetic Prevalence of Autosomal Recessive Congenital Hypothyroidism Based on a General Population Database

Park

2021

Genes

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To assess how genomic information of the general population reflects probabilities of developing diseases and the differences in those probabilities among ethnic groups, a general population database was analyzed with an example of congenital hypothyroidism. Nine candidate genes that follow an autosomal recessive inheritance pattern in congenital hypothyroidism (SLC5A5, TPO, TG, IYD, DUOXA2, DUOX2, TSHR, SLC26A7, GLIS3, FOXE1, TSHB, TRHR) in the gnomAD database (v2.1.1) were analyzed. The carrier frequency (CF) and predicted genetic prevalence (pGP) were estimated. The total CF in the overall population was 3.6%. DUOX2 showed the highest CF (1.8%), followed by TG (0.46%), TPO (0.44%), TSHR (0.31%), SLC26A7 (0.144%), DUOXA2 (0.141%), IYD (0.08%), SLC5A5 (0.06%), TRHR (0.059%), GLIS3 (0.059%), TSHB (0.04%), and FOXE1 (0%). The pGP in the overall population was 9.89 individuals per 100,000 births (1:10,108). The highest pGP was in the East Asian population at 52.48 per 100,000 births (1:1905), followed by Finnish (35.96), Non-Finnish European (9.56), African/African American (4.0), Latino/Admixed American (3.89), South Asian (3.56), and Ashkenazi Jewish (1.81) groups. Comparing the pGP with the real incidence of congenital hypothyroidism, the pGP in East Asian populations was highly consistent with the real incidence.

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Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population

Cited by 19 publications

References 27 publications

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis

Analysis of Worldwide Carrier Frequency and Predicted Genetic Prevalence of Autosomal Recessive Congenital Hypothyroidism Based on a General Population Database

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