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Review of genetics in the United States with emphasis on the prenatal, metabolic, genetic counseling, and training aspects of the field.
Possible latent psychological and social consequences ensuing from genetic screening programs need to be investigated during the planning phase of national genetic screening programs. The relatively few studies which have been performed to determine psychological, social, and economic consequences resulting from a genetic screening program are reviewed. Stigmatization of carrier-status, having major psychosocial implications in heterozygote genetic screening programs, is discussed and related to Erving Goffman's work in the area of stigmatization. Questions are raised regarding the relationship between such variables as religiosity and sex of the individual and acceptance of the status of newly identified carrier of a mutant gene. Severity of the deleterious gene and visibility of the carrier status are two important factors to consider in an estimation of potential stigma. Specific implications are discussed for four genetic diseases: Tay-Sachs, Sickle-Cell Anemia, Huntington's disease and Hemophilia.
The resolution of policy questions relating to medical genetic screening programs will not be without considerable difficulty. Examples include such issues as the optimal degree of screening program expansion, the relative values of screening for different genetic diseases, the appropriate sources of program funding (public vs. private), and the relative value of funding expanded genetic screening programs vs. research directed toward elimination of genetic traits themselves. Information on the net impact of the relevant alternatives is greatly needed, and this need will increase if the National Genetics Act receives funding approval. We have provided what is hopefully a contribution toward this end. While our analysis pertains to a specific disease and a specific screening program for that disease, the methodology is readily generalizable to other genetic diseases, as well as programs of any size or structure. Hopefully, this will serve to stimulate further research efforts that we believe are needed for the objective consideration of resource allocation alternatives.
The wider application of genetic screening is described in four Western Australian populations. Counselling with prenatal diagnosis of Down's syndrome was offered to 57 women over the age of 35 years and less than 16 weeks' gestation who attended an antenatal outpatients department. Forty-four women consented to amniocentesis and two affected fetuses were found. Both public and private patients can be screened to detect fetuses with Down's syndrome. In a population of 200 pregnant girls whose infants were intended for adoption, a specially designed family history form aided identification of genetic disorders in 32 families. Counselling was offered to the biological parents, to the adoptive parents, and, prospectively, to the child in later years. The effectiveness of the family history as a screening device is illustrated in this adoption sample. Counselling of parents of 20 decreased malformed infants initiated the genetic counselling clinic in Western Australia and led to subsequent referral of 92 similar cases by the family doctors. It was found that parents who gave birth to malformed infants welcome information and risk figures. Diagnostic screening in a population of 6000 intellectually handicapped individuals yielded 1372 cases (23%) with Mendelian, multifactorial, or chromosomal modes of inheritance. This screening enabled patients with inherited causes for their intellectual handicap to be identified and placed on a register for health planning.
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OBJECTIVE: Gestational trophoblastic disease (GTD) is characterized genetically by an excess paternal genome and maternal chromosome loss. Intracytoplasmic sperm injection (ICSI) and ICSI with preimplantation genetic screening (PGS) enhance the selection of viable embryos by ensuring that only those with the appropriate genetic makeup are implanted. We aimed to evaluate the pregnancy outcome following ICSI and ICSI/PGS in infertile women with a history of GTDs. MATERIALS AND METHODS: In this retrospective study, we recruited couples who were referred to the Royan Institute with infertility complaints with GTD history from 2010 to 2022. GTD had been confirmed by serial β-human chorionic gonadotrophin (β-hCG) titer, ultrasonography, and histopathology assessment of the evacuated uterine contents. The fluorescent in situ hybridization (FISH) probes were specific for the chromosomes 13, 18, 21, X, and Y. RESULTS: A total of 69 cycles of ICSI (n=41) and ICSI/PGS (n=28) were analyzed. The two treatment groups were comparable in terms of patients' demographic characteristics. The mean number of total retrieved oocytes, MII oocytes, and obtained embryos in the ICSI/PGS cycle was higher compared to the ICSI cycle (P<0.001 for all). Also, a statistically significant difference between groups in the mean number of poor embryos (P=0.004) was found. No statistically significant difference was observed in clinical pregnancy, miscarriage, and live birth rates per embryo transfer (ET) between groups. The findings indicate that 27.2% of embryos exhibited genetic normalcy in the ICSI/PGS group. CONCLUSION: Despite achieving more embryos in ICSI/PGS cycles, the success rates of pregnancy in both groups are approximately the same. Both of these methods can be effective in the management of women with the previous GTD. Considering the high costs and the necessity to eliminate 46XX embryos during PGS procedures, it is advisable to restrict this method to cases with a significant risk of recurrent GTD.
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BACKGROUND AND AIMS: The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS: In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS: Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS: The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.
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Phenotypic screens carried out with functional genomics or small molecules have led to novel biological insights, revealed previously unknown targets for drug discovery programs, and provided starting points for the development of first-in-class therapies. Despite being valuable research tools, genetic and compound screening also have significant limitations. This perspective aims to shed a light on those limitations and provide mitigation strategies when available, with a goal of helping phenotypic screening practitioners gain an understanding of how and when to best utilize either approach.
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Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vitro assays. This initial report describes the results for one of these compounds, Naltrexone. Nalrexone is a relatively nontoxic drug antagonist related to Naloxone which appears to be effective in diminishing the euphoria and dependence upon heroin in clinical studies. With the exception of weak nonspecific DNA damage observed in an E. coli DNA repair test and possibly with WI-38 cells as well, Naltrexone did not demonstrate significant potential for the induction of gene mutations or chromosomal aberrations under the conditions of this evaluation.
BACKGROUND AND OBJECTIVES: Early-onset Parkinson disease (EOPD), defined as symptom onset before 50 years of age, accounts for approximately 10% of patients and is suggested to have a greater genetic component than typical late-onset forms of the disease. Recessive variants in PRKN, PINK1, and DJ-1, are the most common genetic cause of EOPD, however, most studies are in patients of white ancestry. This study aims to analyze genetic variants in PRKN, PINK1, and DJ-1 in Colombian patients to help address the gap in EOPD genetic research of South American populations. METHODS: We analyzed 43 unrelated patients with EOPD using Sanger sequencing for the PRKN, PINK1, and DJ-1 genes and employed multiplex ligation-dependent probe amplification to detect copy number variants. Additionally, long-read whole-genome sequencing was conducted on 3 unresolved patients with age at onset before 30 years of age (long-read sequencing [LRS] patient A-C). RESULTS: We identified known pathogenic single-nucleotide variants and copy number variants in the PRKN gene accounting for 2 patients' disease (4.6% of patients). We observed 2 pathogenic variants in PRKN (c.155delA; p.N52Mfs*29 and c.1083+1G>A) in patient 1, who reported an age at onset of 16 years. We further detected a homozygous duplication of PRKN exons 5-6 in an additional patient, age at onset of 18 years. DISCUSSION: Our study helps characterize genetic contributors to EOPD in Colombian patients, demonstrating genetic forms (PRKN, PINK1, and DJ-1) are rare. Our results highlight a need to include diverse populations in research to improve genetic understanding of disease.
MOTIVATION: Modern single-cell omics data are key to unraveling the complex mechanisms underlying risk for complex diseases revealed by genome-wide association studies (GWAS). Phenotypic screens in model organisms have several important parallels to GWAS which the author explores in this essay. RESULTS: The author provides the historical context of such screens, comparing and contrasting similarities to association studies, and how these screens in model organisms can teach us what to look for. Then the author considers how the results of GWAS might be exhaustively interrogated to interpret the biological mechanisms underpinning disease processes. Finally, the author proposes a general framework for tackling this problem computationally, and explore the data, mechanisms, and technology (both existing and yet to be invented) that are necessary to complete the task. AVAILABILITY AND IMPLEMENTATION: There are no data or code associated with this article.
Forward genetic screens seek to dissect complex biological systems by systematically perturbing genetic elements and observing the resulting phenotypes. While standard screening methodologies introduce individual perturbations, multiplexing perturbations improves the performance of single-target screens and enables combinatorial screens for the study of genetic interactions. Current tools for multiplexing perturbations are limited by technical challenges and do not offer compatibility across diverse screening methodologies, including enrichment, single-cell sequencing, and optical pooled screens. Here, we report the development of CROPseq-multi (CSM), a CROPseq1-inspired lentiviral system to multiplex Streptococcus pyogenes (Sp) Cas9-based perturbations with versatile readout compatibility and high performance for both perturbation and barcode identification. CSM has equivalent per-guide activity to CROPseq and low lentiviral recombination frequencies. Dual-guide CSM libraries are constructed in a single, facile molecular cloning step that facilitates the use of unique molecular identifiers. CSM is compatible with enrichment screening methodologies, single-cell RNA-sequencing readouts, and optical pooled screens. For optical pooled screens, an optimized and multiplexed in situ detection protocol improves barcode counts 10-fold (for mRNA detection), enables detection of recombination events, and reduces the number of sequencing cycles required for decoding by 3-fold relative to CROPseq. CROPseq-multi-v2 (CSMv2) adds compatibility for detection methods based on T7 RNA polymerase in vitro transcription2-5. CSM provides a single system for CRISPR screens that is compatible with individual and combinatorial perturbations, diverse SpCas9-based perturbation technologies, and multiple high-content, single-cell phenotypic readouts.
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SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient's cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.