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1.
Sci Rep ; 14(1): 15342, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961196

RESUMO

Mitochondrial forms account approximately 1-2% of all nonsyndromic cases of hearing loss (HL). One of the most common causative variants of mtDNA is the m.1555A > G variant of the MT-RNR1 gene (OMIM 561000). Currently the detection of the m.1555A > G variant of the MT-RNR1 gene is not included in all research protocols. In this study this variant was screened among 165 patients with HL from the Republic of Buryatia, located in the Baikal Lake region of Russia. In our study, the total contribution of the m.1555A > G variant to the etiology of HL was 12.7% (21/165), while the update global prevalence of this variant is 1.8% (863/47,328). The m.1555A > G variant was notably more prevalent in Buryat (20.2%) than in Russian patients (1.3%). Mitogenome analysis in 14 unrelated Buryat families carrying the m.1555A > G variant revealed a predominant lineage: in 13 families, a cluster affiliated with sub-haplogroup A5b (92.9%) was identified, while one family had the D5a2a1 lineage (7.1%). In a Russian family with the m.1555A > G variant the lineage affiliated with sub-haplogroup F1a1d was found. Considering that more than 90% of Buryat families with the m.1555A > G variant belong to the single maternal lineage cluster we conclude that high prevalence of this variant in patients with HL in the Baikal Lake region can be attributed to a founder effect.


Assuntos
DNA Mitocondrial , Efeito Fundador , Perda Auditiva , Humanos , Federação Russa/epidemiologia , Feminino , Masculino , Perda Auditiva/genética , Perda Auditiva/epidemiologia , Prevalência , DNA Mitocondrial/genética , Adulto , Criança , Adolescente , Haplótipos , Pré-Escolar , Pessoa de Meia-Idade , Lagos , Adulto Jovem
2.
Int J Mol Sci ; 25(12)2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38928478

RESUMO

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9-12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9-12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT-qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9-12 alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9-12 and identifying which of them has developed cancer.


Assuntos
Alelos , Proteína BRCA1 , Síndrome Hereditária de Câncer de Mama e Ovário , Humanos , Proteína BRCA1/genética , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Pessoa de Meia-Idade , Predisposição Genética para Doença , Adulto , Efeito Fundador , Éxons/genética , Neoplasias da Mama/genética , Heterozigoto , Mutação , México , Neoplasias Ovarianas/genética , Relevância Clínica
3.
Dis Model Mech ; 17(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38922202

RESUMO

Founder mutations are disease-causing variants that occur frequently in geographically or culturally isolated groups whose shared ancestor(s) carried the pathogenic variant. While some disease alleles may vanish from the genetic pool due to natural selection, variants with weaker effects may survive for a long time, thereby enhancing the prevalence of some rare diseases. These are predominantly autosomal recessive diseases but can also be autosomal dominant traits with late-onset or mild phenotypes. Cultural practices, such as endogamy and consanguinity, in these isolated groups lead to higher prevalence of such rare diseases compared to the rest of the population and worldwide. In this Perspective, we define population isolates and the underlying genetic mechanisms for accumulating founder mutations. We also discuss the current and potential scientific, clinical and public-health implications of studying founder mutations in population isolates around the world, with a particular focus on the Arab population.


Assuntos
Mundo Árabe , Efeito Fundador , Mutação , Doenças Raras , Humanos , Doenças Raras/genética , Mutação/genética , Árabes/genética
4.
Sci Rep ; 14(1): 13436, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862721

RESUMO

Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder frequently linked to n.72A>G (previously known as n.70A>G and n.71A>G), the most common RMRP variant worldwide. More than 130 pathogenic variants in this gene have already been described associated with CHH, and founder alterations were reported in the Finnish and Japanese populations. Our previous study in Brazilian CHH patients showed a high prevalence of n.197C>T variant (former n.195C>T and n.196C>T) when compared to other populations. The aim of this study was to investigate a possible founder effect of the n.197C>T variant in the RMRP gene in a series of CHH Brazilian patients. We have selected four TAG SNPs within chromosome 9 and genotyped the probands and their parents (23 patients previously described and nine novel). A common haplotype to the n.197C>T variant carriers was identified. Patients were also characterized for 46 autosomal Ancestry Informative Markers (AIMs). European ancestry was the most prevalent (58%), followed by African (24%) and Native American (18%). Our results strengthen the hypothesis of a founder effect for the n.197C>T variant in Brazil and indicate that this variant in the RMRP gene originated from a single event on chromosome 9 with a possible European origin.


Assuntos
Efeito Fundador , Cabelo , Doença de Hirschsprung , Osteocondrodisplasias , Polimorfismo de Nucleotídeo Único , Humanos , Brasil , Doença de Hirschsprung/genética , Masculino , Osteocondrodisplasias/genética , Osteocondrodisplasias/congênito , Feminino , Cabelo/anormalidades , RNA Longo não Codificante/genética , Haplótipos , Doenças da Imunodeficiência Primária/genética , Hipotricose/genética , Cromossomos Humanos Par 9/genética , Criança
5.
Genome Biol Evol ; 16(7)2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38913571

RESUMO

Dingoes come from an ancient canid lineage that originated in East Asia around 8,000 to 11,000 years BP. As Australia's largest terrestrial predator, dingoes play an important ecological role. A small, protected population exists on a world heritage listed offshore island, K'gari (formerly Fraser Island). Concern regarding the persistence of dingoes on K'gari has risen due to their low genetic diversity and elevated inbreeding levels. However, whole-genome sequence data is lacking from this population. Here, we include five new whole-genome sequences of K'gari dingoes. We analyze a total of 18 whole-genome sequences of dingoes sampled from mainland Australia and K'gari to assess the genomic consequences of their demographic histories. Long (>1 Mb) runs of homozygosity (ROHs)-indicators of inbreeding-are elevated in all sampled dingoes. However, K'gari dingoes showed significantly higher levels of very long ROH (>5 Mb), providing genomic evidence for small population size, isolation, inbreeding, and a strong founder effect. Our results suggest that, despite current levels of inbreeding, the K'gari population is purging strongly deleterious mutations, which, in the absence of further reductions in population size, may facilitate the persistence of small populations despite low genetic diversity and isolation. However, there may be little to no purging of mildly deleterious alleles, which may have important long-term consequences, and should be considered by conservation and management programs.


Assuntos
Endogamia , Ilhas , Animais , Austrália , Efeito Fundador , Variação Genética , Isolamento Reprodutivo , Genética Populacional , Homozigoto , Genoma
6.
Tunis Med ; 102(5): 256-265, 2024 May 05.
Artigo em Francês | MEDLINE | ID: mdl-38801282

RESUMO

The genetic disease spectrum in Tunisia arises from the founder effect, genetic drift, selection, and consanguinity. The latter represents a deviation from panmixia, characterized by a non-random matrimonial choice that may be subject to several rules, such as socio-cultural, economic, or other factors. This shifts the genetic structure away from the Hardy-Weinberg equilibrium, increasing homozygous genotypes and decreasing heterozygotes, thus raising the frequency of autosomal recessive diseases. Similar to other Arab populations, Tunisia displays high consanguinity rates that vary geographically. Approximately 60% of reported diseases in Tunisia are autosomal recessive, with consanguinity possibly occurring in 80% of families for a specific disease. In inbred populations, consanguinity amplifies autosomal recessive disease risk, yet it does not influence autosomal dominant disease likelihood but rather impacts its phenotype. Consanguinity is also suggested to be a major factor in the homozygosity of deleterious variants leading to comorbid expression. At the genome level, inbred individuals inherit homozygous mutations and adjacent genomic regions known as runs of homozygosity (ROHs). Short ROHs indicate distant inbreeding, while long ROHs refer to recent inbreeding. ROHs are distributed rather irregularly across the genome, with certain short regions featuring an excess of ROH, known as ROH islands. In this review, we discuss consanguinity's impact on population health and genome dynamics, using Tunisia as a model.


Assuntos
Consanguinidade , Tunísia/epidemiologia , Humanos , Genoma Humano , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/diagnóstico , Homozigoto , Efeito Fundador
7.
J Clin Immunol ; 44(5): 121, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758287

RESUMO

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Efeito Fundador , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Masculino , Feminino , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Haplótipos , Mutação/genética , Ásia Oriental , Alelos , Candida albicans/genética , Adulto , Linhagem , Povo Asiático/genética
8.
Acta Biotheor ; 72(2): 6, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38819710

RESUMO

The Y chromosome in the XY sex-determination system is often shorter than its X counterpart, a condition attributed to degeneration after Y recombination ceases. Contrary to the traditional view of continuous, gradual degeneration, our study reveals stabilization within large mating populations. In these populations, we demonstrate that both mutant and active alleles on the Y chromosome can reach equilibrium through a mutation-selection balance. However, the emergence of a new species, particularly through the founder effect, can disrupt this equilibrium. Specifically, if the male founders of a new species carry only a mutant allele for a particular Y-linked gene, this allele becomes fixed, leading to the loss of the corresponding active gene on the Y chromosome. Our findings suggest that the rate of Y-chromosome degeneration may be linked to the frequency of speciation events associated with single-male founder events.


Assuntos
Efeito Fundador , Cromossomo Y , Masculino , Cromossomo Y/genética , Animais , Alelos , Especiação Genética , Mutação , Feminino , Humanos , Modelos Genéticos
9.
Genes (Basel) ; 15(5)2024 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-38790275

RESUMO

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS). Following five rounds of calibration of NGS-based steps, CDIP was used in 740 IRD samples. The analysis revealed 151 mutations in 131 index cases. In 54 (7%) of these cases, CDIP identified the genetic cause of disease (the remaining were single-heterozygous recessive mutations). These include a patient that was clinically diagnosed with retinoschisis and found to be homozygous for NR2E3-c.932G>A (p.R311Q), and a patient with RP who is hemizygous for an RPGR variant, c.292C>A (p.H98N), which was not included in the analysis but is located in proximity to one of these mutations. CDIP is a cost-effective deep sequencing panel for simultaneous detection of common founder mutations. This protocol can be implemented for additional populations as well as additional inherited diseases, and mainly in populations with strong founder effects.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/economia , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Efeito Fundador , Masculino , Feminino , Testes Genéticos/métodos , Testes Genéticos/economia , Análise Custo-Benefício , Linhagem
10.
Mol Biol Evol ; 41(5)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38743590

RESUMO

Studying range expansions is central for understanding genetic variation through space and time as well as for identifying refugia and biological invasions. Range expansions are characterized by serial founder events causing clines of decreasing genetic diversity away from the center of origin and asymmetries in the two-dimensional allele frequency spectra. These asymmetries, summarized by the directionality index (ψ), are sensitive to range expansions and persist for longer than clines in genetic diversity. In continuous and finite meta-populations, genetic drift tends to be stronger at the edges of the species distribution in equilibrium populations and populations undergoing range expansions alike. Such boundary effects are expected to affect geographic patterns in genetic diversity and ψ. Here we demonstrate that boundary effects cause high false positive rates in equilibrium meta-populations when testing for range expansions. In the simulations, the absolute value of ψ (|ψ|) in equilibrium data sets was proportional to the fixation index (FST). By fitting signatures of range expansions as a function of ɛ |ψ|/FST and geographic clines in ψ, strong evidence for range expansions could be detected in data from a recent rapid invasion of the cane toad, Rhinella marina, in Australia, but not in 28 previously published empirical data sets from Australian scincid lizards that were significant for the standard range expansion tests. Thus, while clinal variation in ψ is still the most sensitive statistic to range expansions, to detect true signatures of range expansions in natural populations, its magnitude needs to be considered in relation to the overall levels of genetic structuring in the data.


Assuntos
Genética Populacional , Animais , Genética Populacional/métodos , Modelos Genéticos , Variação Genética , Espécies Introduzidas , Austrália , Deriva Genética , Frequência do Gene , Efeito Fundador
11.
J Hered ; 115(4): 411-423, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38624218

RESUMO

The first record of captive-bred red foxes (Vulpes vulpes) dates to 1896 when a breeding enterprise emerged in the provinces of Atlantic Canada. Because its domestication happened during recent history, the red fox offers a unique opportunity to examine the genetic diversity of an emerging domesticated species in the context of documented historical and economic influences. In particular, the historical record suggests that North American and Eurasian farm-bred populations likely experienced different demographic trajectories. Here, we focus on the likely impacts of founder effects and genetic drift given historical trends in fox farming on North American and Eurasian farms. A total of 15 mitochondrial haplotypes were identified in 369 foxes from 10 farm populations that we genotyped (n = 161) or that were previously published. All haplotypes are endemic to North America. Although most haplotypes were consistent with eastern Canadian ancestry, a small number of foxes carried haplotypes typically found in Alaska and other regions of western North America. The presence of these haplotypes supports historical reports of wild foxes outside of Atlantic Canada being introduced into the breeding stock. These putative Alaskan and Western haplotypes were more frequently identified in Eurasian farms compared to North American farms, consistent with historical documentation suggesting that Eurasian economic and breeding practices were likely to maintain low-frequency haplotypes more effectively than in North America. Contextualizing inter- vs. intra-farm genetic diversity alongside the historical record is critical to understanding the origins of this emerging domesticate and the relationships between wild and farm-bred fox populations.


Assuntos
Raposas , Variação Genética , Haplótipos , Raposas/genética , Animais , DNA Mitocondrial/genética , Canadá , Genética Populacional , Animais Domésticos/genética , Domesticação , Cruzamento , Efeito Fundador , Deriva Genética , Fazendas
12.
Nat Commun ; 15(1): 3608, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38684711

RESUMO

Invasive populations often experience founder effects: a loss of genetic diversity relative to the source population, due to a small number of founders. Even where these founder effects do not impact colonization success, theory predicts they might affect the rate at which invasive populations expand. This is because secondary founder effects are generated at advancing population edges, further reducing local genetic diversity and elevating genetic load. We show that in an expanding invasive population of the Asian honey bee (Apis cerana), genetic diversity is indeed lowest at range edges, including at the complementary sex determiner, csd, a locus that is homozygous-lethal. Consistent with lower local csd diversity, range edge colonies had lower brood viability than colonies in the range centre. Further, simulations of a newly-founded and expanding honey bee population corroborate the spatial patterns in mean colony fitness observed in our empirical data and show that such genetic load at range edges will slow the rate of population expansion.


Assuntos
Efeito Fundador , Variação Genética , Espécies Introduzidas , Animais , Abelhas/genética , Abelhas/fisiologia , Masculino , Feminino , Dinâmica Populacional , Comportamento Social
13.
Am J Med Genet A ; 194(8): e63592, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38568023

RESUMO

Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.


Assuntos
Artrogripose , Efeito Fundador , Fenótipo , Humanos , Artrogripose/genética , Artrogripose/patologia , Masculino , Feminino , Índia , Criança , Pré-Escolar , Linhagem , Adolescente , Mutação/genética , Lactente , Estudos de Associação Genética , Estudos de Coortes , Genótipo , Adulto , Metaloendopeptidases
14.
Nature ; 628(8009): 844-853, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570685

RESUMO

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.


Assuntos
Alelos , DNA Polimerase gama , Vírus da Encefalite Transmitidos por Carrapatos , Herpesvirus Humano 1 , Tolerância Imunológica , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Camundongos , Idade de Início , COVID-19/imunologia , COVID-19/virologia , COVID-19/genética , DNA Polimerase gama/genética , DNA Polimerase gama/imunologia , DNA Polimerase gama/metabolismo , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Mutação , RNA Mitocondrial/imunologia , RNA Mitocondrial/metabolismo , SARS-CoV-2/imunologia
15.
Animal ; 18(5): 101148, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38642411

RESUMO

With a history tracing back to at least the 18th century and a substantial global influence on various breeds, Polish Arabian horse population is of paramount importance for both breeders and conservationists. However, its genetic makeup and the population dynamics are still not well understood. This study presents an analysis of the modern Polish Arabian horse population using pedigree data, focusing on the breed's genetic diversity and population structure. Our analysis encompassed 1 498 individuals defined as the reference population (RP) and their 11 065 ancestors, which resulted in the dataset of 12 254 individuals (total population). We traced their genealogy to assess inbreeding coefficients (F), founder effects, and genetic variability measures such as the effective number of founders (fe), ancestors (fa), or founder genome equivalents (fge). The results indicated a good pedigree quality with an average of 28.1 maximum traced generations, revealing high pedigree completeness for initial generations with a decline beyond the seventh generation. The genetic diversity parameters showed a considerable bottleneck effect, with an effective number of founders at 73, which reflects a substantial loss of genetic diversity over time. Despite the vast total number of founders (852), only a few have had a lasting impact on the current population, signaling the need for revised breeding strategies to maintain diversity. The study identified a slight but consistent rise in inbreeding over the last century, with a marginal recent decline, and a significant difference in the contribution of various founders. The average F was 5.8%, with 99.6% of the reference population being inbred. The analysis of effective population size (Ne) highlighted potential risks for genetic diversity, urging for revision of breeding goals to consider a wider array of founder lineages. The study indicated that stallions belonging to RP can be attributed to 15 distinct sirelines, whereas mares to 45 unique damlines, more than considered in the current breeding program (8 and 15, respectively). Conclusively, the study underlines the need for ongoing monitoring and strategic breeding to maintain and enhance the genetic diversity of Polish Arabians, considering the breed's historical significance and contemporary genetic challenges.


Assuntos
Variação Genética , Endogamia , Linhagem , Animais , Cavalos/genética , Polônia , Masculino , Feminino , Cruzamento , Efeito Fundador , Genética Populacional , Dinâmica Populacional
16.
Hum Genet ; 143(3): 423-435, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38519595

RESUMO

Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.


Assuntos
Frequência do Gene , Doença de Meniere , Mutação de Sentido Incorreto , População Branca , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Europa (Continente)/epidemiologia , Efeito Fundador , Ligação Genética , Predisposição Genética para Doença , Doença de Meniere/genética , Doença de Meniere/epidemiologia , Prevalência , População Branca/genética , População Europeia
17.
Arch Med Res ; 55(3): 102971, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38513336

RESUMO

INTRODUCTION: In Mexico, familial hypercholesterolemia (FH) is underdiagnosed, but population screening in small communities where at least one homozygous patient has already been detected results in a useful and inexpensive approach to reduce this problem. Considering that we previously reported nine homozygous cases from the state of Oaxaca, we decided to perform a population screening to identify patients with FH and to describe both their biochemical and genetic characteristics. METHODS: LDL cholesterol (LDLc) was quantified in 2,093 individuals from 11 communities in Oaxaca; either adults with LDLc levels ≥170 mg/dL or children with LDLc ≥130 mg/dL were classified as suggestive of FH and therefore included in the genetic study. LDLR and APOB (547bp fragment of exon 26) genes were screened by sequencing and MLPA analysis. RESULTS: Two hundred and five individuals had suggestive FH, with a mean LDLc of 223 ± 54 mg/dL (range: 131-383 mg/dL). Two pathogenic variants in the LDLR gene were detected in 149 individuals: c.-139_-130del (n = 1) and c.2271del (n = 148). All patients had a heterozygous genotype. With the cascade screening of their relatives (n = 177), 15 heterozygous individuals for the c.2271del variant were identified, presenting a mean LDLc of 133 ± 35 mg/dL (range: 60-168 mg/dL). CONCLUSIONS: The FH frequency in this study was 7.8% (164/2093), the highest reported worldwide. A founder effect combined with inbreeding could be responsible for the high percentage of patients with the LDLR c.2271del variant (99.4%), which allowed us to detect both significant biochemical heterogeneity and incomplete penetrance; hence, we assumed the presence of phenotype-modifying variants.


Assuntos
Efeito Fundador , Hiperlipoproteinemia Tipo II , Adulto , Criança , Humanos , LDL-Colesterol , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , México/epidemiologia , Mutação , Fenótipo , Prevalência , Receptores de LDL/genética
18.
Clin Genet ; 106(1): 66-71, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38417950

RESUMO

Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a genetically heterogeneous multiple congenital malformation syndrome. Although pathogenic variants in RARB and STRA6 are established causes of PDAC, many PDAC cases remain unsolved at the molecular level. Recently, we proposed biallelic WNT7B variants as a novel etiology based on several families with typical features of PDAC syndrome albeit with variable expressivity. Here, we report three patients from two families that share a novel founder variant in WNT7B (c.739C > T; Arg247Trp). The phenotypic expression of this variant ranges from typical PDAC features to isolated genitourinary anomalies. Similar to previously reported PDAC-associated WNT7B variants, this variant was found to significantly impair WNT7B signaling activity further corroborating its proposed pathogenicity. This report adds further evidence to WNT7B-related PDAC and expands its variable expressivity.


Assuntos
Fenótipo , Proteínas Wnt , Humanos , Proteínas Wnt/genética , Masculino , Feminino , Anoftalmia/genética , Anoftalmia/patologia , Microftalmia/genética , Microftalmia/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Efeito Fundador , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Linhagem , Mutação , Predisposição Genética para Doença , Síndrome , Pulmão/patologia , Pulmão/anormalidades
19.
J Hum Genet ; 69(6): 235-244, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38424183

RESUMO

Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.


Assuntos
Haplótipos , Proteoglicanas de Heparan Sulfato , Osteocondrodisplasias , Feminino , Humanos , Masculino , Alelos , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Efeito Fundador , Proteoglicanas de Heparan Sulfato/genética , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Doenças Fetais
20.
Medicina (Kaunas) ; 60(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38399542

RESUMO

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.


Assuntos
Distrofias de Cones e Bastonetes , Retinose Pigmentar , Humanos , Distrofias de Cones e Bastonetes/genética , Sicília/epidemiologia , Efeito Fundador , Proteínas do Olho , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Fenótipo , Linhagem , Mutação , Análise Mutacional de DNA , Proteínas Associadas aos Microtúbulos/genética
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