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HGG Advances Oct 2023Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at...
Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: , associated with Fabry disease, and , associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in or . We identified three individuals (2 male, 1 female) with PLPVs in , all of whom were undiagnosed, and three individuals (3 female) with PLPVs in , two of whom were undiagnosed. All three individuals with PLPVs in (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that and variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.
Topics: Female; Male; Humans; Fabry Disease; Phenotype; Genotype; Penetrance; Hospitals
PubMed: 37593415
DOI: 10.1016/j.xhgg.2023.100226 -
Current Opinion in Immunology Dec 2015Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the... (Review)
Review
Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the populations in developed countries age, these chronic diseases will become an increasing burden in human suffering and health care costs. By contrast, rare immune diseases that are severe and develop early in childhood are frequently monogenic and fully penetrant, often with a Mendelian inheritance pattern. Although these may be incompatible with survival or cured by hematopoietic stem cell transplantation, we will argue that they constitute a rich source of genetic insights into immunological diseases. Here, we discuss five examples of well-studied Mendelian disease-causing genes and their known or predicted roles in conferring susceptibility to common, polygenic diseases of autoimmunity. Mendelian disease mutations, as experiments of nature, reveal human loci that are indispensable for immune regulation and, therefore, most promising as therapeutic targets.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Disease Susceptibility; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Immunomodulation; Mendelian Randomization Analysis; Mutation; Penetrance; Polymorphism, Genetic
PubMed: 26433354
DOI: 10.1016/j.coi.2015.09.001 -
JAMA Oncology Apr 2018
Topics: Bias; Breast Neoplasms; Humans; Pedigree; Penetrance
PubMed: 29285541
DOI: 10.1001/jamaoncol.2017.4573 -
Human Genetics Jun 2020Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are... (Review)
Review
Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.
Topics: Epigenesis, Genetic; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Mosaicism; Penetrance; Primary Immunodeficiency Diseases
PubMed: 32067110
DOI: 10.1007/s00439-020-02131-9 -
Developmental Dynamics : An Official... Aug 2019Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and... (Review)
Review
Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and abnormal. Standard genetic approaches, particularly useful in understanding monogenic diseases, are no longer sufficient as research attention shifts toward multifactorial outcomes. Here, we examine this progression through the lens of holoprosencephaly (HPE), a common human malformation involving incomplete forebrain division, and a classic example of an etiologically complex outcome. We relate the basic underpinning of HPE pathogenesis to critical cell-cell interactions and signaling molecules discovered through embryological and genetic approaches in multiple model organisms, and discuss the role of the mouse model in functional examination of HPE-linked genes. We then outline the most critical remaining gaps to understanding human HPE, including the conundrum of incomplete penetrance/expressivity and the role of gene-environment interactions. To tackle these challenges, we outline a strategy that leverages new and emerging technologies in multiple model systems to solve the puzzle of HPE.
Topics: Animals; Gene-Environment Interaction; Holoprosencephaly; Humans; Mice; Models, Animal; Penetrance; Prosencephalon; Signal Transduction
PubMed: 30993762
DOI: 10.1002/dvdy.41 -
Tremor and Other Hyperkinetic Movements... Nov 2020Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in , a maternally imprinted gene, are the most frequent...
BACKGROUND
Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in , a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of -linked M-D is unknown, the pathogenicity of variants identified in patients with M-D may be indeterminant, and variants predicted to be deleterious by analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies.
METHODS
variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated pathogenic variants.
RESULTS
Within gnomAD v2, there were 56, 408, and 1250 alleles harboring variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an variant with a CADD score ≥ 25.
DISCUSSION
M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees.
HIGHLIGHTS
analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.
Topics: Computer Simulation; Databases, Genetic; Dystonic Disorders; Genetic Testing; Health Services Accessibility; Humans; Mutation; Penetrance; Phenotype; Polymorphism, Single Nucleotide; Prevalence; Sarcoglycans; Exome Sequencing; Whole Genome Sequencing
PubMed: 33200041
DOI: 10.5334/tohm.567 -
Movement Disorders : Official Journal... Jun 2021The THAP1 gene encodes a transcription factor, and pathogenic variants cause a form of autosomal dominant, isolated dystonia (DYT-THAP1) with reduced penetrance. Factors...
BACKGROUND
The THAP1 gene encodes a transcription factor, and pathogenic variants cause a form of autosomal dominant, isolated dystonia (DYT-THAP1) with reduced penetrance. Factors underlying both reduced penetrance and the disease mechanism of DYT-THAP1 are largely unknown.
METHODS
We performed transcriptome analysis on 29 cortical neuronal precursors derived from human-induced pluripotent stem cell lines generated from manifesting and nonmanifesting THAP1 mutation carriers and control individuals.
RESULTS
Whole transcriptome analysis showed a penetrance-linked signature with expressional changes more pronounced in the group of manifesting (MMCs) than in nonmanifesting mutation carriers (NMCs) when compared to controls. A direct comparison of the transcriptomes in MMCs versus NMCs showed significant upregulation of the DRD4 gene in MMCs. A gene set enrichment analysis demonstrated alterations in various neurotransmitter release cycle pathways, extracellular matrix organization, and deoxyribonucleic acid methylation between MMCs and NMCs. When specifically considering transcription factors, the expression of YY1 and SIX2 differed in MMCs versus NMCs. Further, THAP1 was upregulated in the group of MMCs.
CONCLUSIONS
To our knowledge, this is the first report systematically analyzing reduced penetrance in DYT-THAP1 in a human model using transcriptomes. Our findings indicate that transcriptional alterations during cortical development influence DYT-THAP1 pathogenesis and penetrance. We reinforce previously linked pathways including dopamine and eukaryotic translation initiation factor 2 alpha signaling in the pathogenesis of dystonia including DYT-THAP1 and suggest extracellular matrix organization and deoxyribonucleic acid methylation as mediators of disease protection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Apoptosis Regulatory Proteins; DNA-Binding Proteins; Humans; Induced Pluripotent Stem Cells; Mutation; Penetrance
PubMed: 33547842
DOI: 10.1002/mds.28506 -
Journal of Medical Genetics Jun 2021Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA.
METHODS
Through systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG) in the AR gene between patients and 112 248 control alleles of the general population.
RESULTS
Our analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG) ≥35 present in 107/100,000 and (CAG) ≥38 present in 27/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG), above which it reaches a plateau approaching maximum value.
CONCLUSION
Asymptomatic men of the general population with no/unknown SBMA family history are free of risk when carrying (CAG) ≤34, are at intermediate but increasing risk for developing SBMA when carrying (CAG) ≈35-46 and have close to 100% risk of developing the disease when carrying (CAG) ≥47. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles.
Topics: Age of Onset; Alleles; Bulbo-Spinal Atrophy, X-Linked; Female; Gene Frequency; Humans; Meiosis; Models, Genetic; Penetrance
PubMed: 32571900
DOI: 10.1136/jmedgenet-2020-106963 -
European Heart Journal Apr 2020We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a...
AIMS
We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study.
METHODS AND RESULTS
Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5-9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (-0.6%/year vs. -0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47-182.81, P < 0.01).
CONCLUSION
More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events.
Topics: Adult; Arrhythmogenic Right Ventricular Dysplasia; Disease Progression; Family; Female; Humans; Longitudinal Studies; Male; Middle Aged; Penetrance; Young Adult
PubMed: 31504415
DOI: 10.1093/eurheartj/ehz570 -
Genes Jul 2023Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes...
Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes and , many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ( = 4), ( = 5), ( = 2), ( = 1), and ( = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing alone.
Topics: Humans; Female; Breast Neoplasms; BRCA1 Protein; Penetrance; BRCA2 Protein; Kidney Neoplasms
PubMed: 37628581
DOI: 10.3390/genes14081530