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PLoS Genetics Oct 2019Limited translational genomic research data have been reported on the application of exome sequencing and parallel gene testing for preconception carrier screening...
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.
Limited translational genomic research data have been reported on the application of exome sequencing and parallel gene testing for preconception carrier screening (PCS). Here, we present individual-level data from a large PCS program in which exome sequencing was routinely performed on either gamete donors (5,845) or infertile patients (8,280) undergoing in vitro fertilization (IVF) treatment without any known family history of inheritable genetic conditions. Individual-level data on pathogenic variants were used to define conditions for PCS based on criteria for severity, penetrance, inheritance pattern, and age of onset. Fetal risk was defined based on actual carrier frequency data accounting for the specific inheritance pattern (fetal disease risk, FDR). In addition, large-scale application of exome sequencing for PCS allowed a deep investigation of the incidence of medically actionable secondary findings in this population. Exome sequencing achieved remarkable clinical sensitivity for reproductive risk of highly penetrant childhood-onset disorders (1/337 conceptions) through analysis of 114 selected gene-condition pairs. A significant contribution to fetal disease risk was observed for rare (carrier rate < 1:100) and X-linked conditions (16.7% and 41.2% of total FDR, respectively). Subgroup analysis of 776 IVF couples identified 37 at increased reproductive risk (4.8%; 95% CI = 3.4-6.5). Further, two additional couples had increased risk for very rare conditions when both members of a parental pair were treated as a unit and the search was extended to the entire exome. About 2.3% of participants showed at least one pathogenic variant for genes included in the updated American College of Medical Genetics and Genomics v2.0 list of secondary findings. Gamete donors and IVF couples showed similar carrier burden for both carrier screening and secondary findings, indicating no causal relationship to fertility. These translational research data will facilitate development of more effective PCS strategies that maximize clinical sensitivity with minimal counterproductive effects.
Topics: Adult; Child; Child, Preschool; Directed Tissue Donation; Exome; Female; Genes, Recessive; Genetic Carrier Screening; Genetic Predisposition to Disease; Genetic Testing; Genome, Human; Genomics; Heterozygote; Humans; Infant; Infant, Newborn; Infertility; Male; Mutation; Translational Research, Biomedical; Exome Sequencing
PubMed: 31589614
DOI: 10.1371/journal.pgen.1008409 -
Proceedings of the National Academy of... Feb 2020One 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...
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.
Topics: Africa; Asia; Europe; Gene Frequency; Genes, Recessive; Heterozygote; Humans; Mutation; Pedigree; Prevalence; Retinal Diseases
PubMed: 31964843
DOI: 10.1073/pnas.1913179117 -
Annual Review of Medicine Jan 2022Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in , the cystic fibrosis transmembrane conductance regulator gene. People with CF... (Review)
Review
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in , the cystic fibrosis transmembrane conductance regulator gene. People with CF experience a wide variety of medical conditions that affect the pulmonary, endocrine, gastrointestinal, pancreatic, biliary, and reproductive systems. Traditionally, CF carriers, with one defective copy of , were not thought to be at risk for CF-associated diseases. However, an emerging body of literature suggests that heterozygotes are at increased risk for many of the same conditions as homozygotes. For example, heterozygotes appear to be at increased risk for chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis. In the United States alone, there are almost 10 million CF carriers. Universal newborn screening and prenatal genetic screening will identify more. Thus, there is a critical need to develop more precise estimates of health risks attributable to the CF carrier state across the lifespan.
Topics: Cystic Fibrosis; Female; Genetic Testing; Heterozygote; Humans; Infant, Newborn; Mutation; Neonatal Screening; Phenotype; Pregnancy
PubMed: 35084992
DOI: 10.1146/annurev-med-042120-020148 -
Science Translational Medicine Jan 2011Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases...
Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160x average target coverage, 93% of nucleotides had at least 20x coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.
Topics: Base Sequence; Child; Databases, Genetic; Female; Genes, Recessive; Genetic Carrier Screening; Genetic Testing; Genome, Human; Heterozygote; Humans; Molecular Sequence Data; Mutation; Pregnancy; Prenatal Diagnosis; Sequence Alignment; Sequence Analysis, DNA
PubMed: 21228398
DOI: 10.1126/scitranslmed.3001756 -
Journal of the American Society of... Oct 2015Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified:...
Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Genetic Association Studies; Heterozygote; Humans; Hyperoxaluria, Primary; Infant; Middle Aged; Young Adult
PubMed: 25644115
DOI: 10.1681/ASN.2014070698 -
Proceedings of the National Academy of... Jan 2020Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk...
Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk ( < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers ( < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.
Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Female; Genetic Carrier Screening; Genetic Testing; Heterozygote; Humans; Infant; Infant, Newborn; Male; Middle Aged; Molecular Epidemiology; Mutation; Prevalence; Retrospective Studies; United States; Young Adult
PubMed: 31882447
DOI: 10.1073/pnas.1914912117 -
Genetics in Medicine : Official Journal... Mar 2013Recent developments in genomics have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology...
PURPOSE
Recent developments in genomics have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology enables simultaneous measurement of carrier frequencies for many diseases. As the resultant rank-ordering of carrier frequencies impacts the design and prioritization of screening programs, the accuracy of this ranking is a public health concern.
METHODS
A total of 23,453 individuals from many obstetric, genetics, and infertility clinics were referred for routine recessive disease carrier screening. Multiplex carrier screening was performed and results were aggregated for this study.
RESULTS
Twenty-four percent of individuals were identified as carriers for at least one of 108 disorders, and 5.2% were carriers for multiple disorders. We report tabulations of carrier frequency by self-identified ethnicity and disease.
CONCLUSION
To our knowledge, this study of a large, ethnically diverse clinical sample provides the most accurate measurements to date of carrier frequencies for hundreds of recessive alleles. The study also yields information on the clinical considerations associated with routine use of expanded panels and provides support for a pan-ethnic screening paradigm that minimizes the use of "racial" categories by the physician, as recommended by recent guidelines.
Topics: Adolescent; Adult; Ethnicity; Female; Gene Frequency; Genetic Carrier Screening; Genetic Diseases, Inborn; Heterozygote; Humans; Male; Middle Aged; Young Adult
PubMed: 22975760
DOI: 10.1038/gim.2012.114 -
Journal of Medical Genetics Jun 2007Recent methodological advances have improved the detection rate for dystrophin mutations, but there are no published studies that have measured the clinical utility of...
BACKGROUND
Recent methodological advances have improved the detection rate for dystrophin mutations, but there are no published studies that have measured the clinical utility of these protocols for carrier detection compared with conventional carrier testing protocols that use pedigree, serum creatine kinase levels and linkage analysis.
METHODS AND SUBJECTS
The clinical utility of a combined mutation detection protocol was measured. It involved quantitative PCR procedures followed by DNA sequence analysis for the identification of dystrophin mutation carriers in 2101 women at risk of being carriers from 348 mutation-known Duchenne or Becker muscular dystrophy pedigrees.
RESULTS
The combined mutation detection protocol identified a mutation in 96% and 82% of index cases of Duchenne muscular dystrophy and Becker muscular dystrophy, respectively. An additional 692 (33%) potential carriers were correctly classified by the combined mutation detection protocol compared with pedigree, serum creatine kinase levels and linkage analysis. Significantly lower mutation carrier rates were identified in the mothers of isolated cases with deletion mutations than predicted from theoretical considerations, but these findings were not confirmed for duplication and DNA sequence mutations.
CONCLUSIONS
There are significant clinical benefits to be gained from a combined mutation detection protocol for carrier detection. It is recommended that mutation-specific carrier frequencies for the different classes of dystrophin mutations should be taken into account in genetic counselling practice.
Topics: Female; Genetic Carrier Screening; Heterozygote; Humans; Male; Mothers; Muscular Dystrophy, Duchenne; Mutation
PubMed: 17259292
DOI: 10.1136/jmg.2006.047464 -
Molecular Oncology Jun 2010Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high... (Review)
Review
Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in BRCA1 and BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from BRCA1 and BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.
Topics: Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Humans; Mutation; Penetrance; Polymorphism, Genetic
PubMed: 20542480
DOI: 10.1016/j.molonc.2010.04.011 -
International Journal of Molecular... Mar 2023Inbreeding is the crossing of closely related individuals in nature or a plantation or self-pollinating plants, which produces plants with high homozygosity. This... (Review)
Review
Inbreeding is the crossing of closely related individuals in nature or a plantation or self-pollinating plants, which produces plants with high homozygosity. This process can reduce genetic diversity in the offspring and decrease heterozygosity, whereas inbred depression (ID) can often reduce viability. Inbred depression is common in plants and animals and has played a significant role in evolution. In the review, we aim to show that inbreeding can, through the action of epigenetic mechanisms, affect gene expression, resulting in changes in the metabolism and phenotype of organisms. This is particularly important in plant breeding because epigenetic profiles can be linked to the deterioration or improvement of agriculturally important characteristics.
Topics: Animals; Inbreeding; Plant Breeding; Epigenesis, Genetic; Plants; Heterozygote
PubMed: 36982483
DOI: 10.3390/ijms24065407