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Annals of the New York Academy of... Dec 2021Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms... (Review)
Review
Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.
Topics: Congresses as Topic; Genetic Variation; Humans; Mental Disorders; Neurodevelopmental Disorders; Penetrance; Research Report
PubMed: 34342000
DOI: 10.1111/nyas.14658 -
Genetics in Medicine : Official Journal... Jul 2021We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR).
PURPOSE
We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR).
METHODS
Participants (n = 2,535) with hypercholesterolemia and/or colon polyps underwent targeted sequencing of 68 genes and 14 single-nucleotide variants. Penetrance was estimated based on presence of relevant traits in the electronic health record (EHR). Outcomes occurring within 1-year of RoR were ascertained by EHR review. Analyses were stratified by tier 1 and non-tier 1 disorders.
RESULTS
Actionable findings were present in 122 individuals and results were disclosed to 98. The average penetrance for tier 1 disorder variants (67%; n = 58 individuals) was higher than in non-tier 1 variants (46.5%; n = 58 individuals). After excluding 45 individuals (decedents, nonresponders, known genetic diagnoses, mosaicism), ≥1 outcomes were noted in 83% of 77 participants following RoR; 78% had a process outcome (referral to a specialist, new testing, surveillance initiated); 68% had an intermediate outcome (new test finding or diagnosis); 19% had a clinical outcome (therapy modified, risk reduction surgery). Risk reduction surgery occurred more often in participants with tier 1 than those with non-tier 1 variants.
CONCLUSION
Relevant phenotypic traits were observed in 57% whereas a clinical outcome occurred in 19% of participants with actionable genomic variants in the year following RoR.
Topics: Genome; Genomics; Humans; Penetrance; Phenotype
PubMed: 33824501
DOI: 10.1038/s41436-021-01142-9 -
International Journal of Molecular... Apr 2023Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern....
Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in (c.960G>A, p.Met320Ile), (c.208G>A, p.Gly70Arg), and (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the (c.163del, p.Ile55*), (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), (c.1106C>T, p.Ala369Val), and (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, (p.Gly70Arg), (p.Leu145Arg), and p.(Thr917Met). Except for , where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the gene. The molecular modeling results suggest that the VUS of the (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the (c.960G>A, p.Met320Ile) and (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.
Topics: Humans; Hypogonadism; Kallmann Syndrome; Phenotype; Heterozygote; Penetrance; Mutation
PubMed: 37108593
DOI: 10.3390/ijms24087428 -
Schizophrenia Bulletin Jul 2008The evolutionary origins of one of the most dramatic and seemingly deleterious behavioral phenotypes, the syndrome known as schizophrenia, are mysterious. Schizophrenia... (Review)
Review
The evolutionary origins of one of the most dramatic and seemingly deleterious behavioral phenotypes, the syndrome known as schizophrenia, are mysterious. Schizophrenia occurs in all cultures and is inherited. Although most phenotypes are said to be "selected for" based on adaptive qualities, it is difficult to understand how the genetic basis of schizophrenia could have operated under a similar framework. This has lead several theorists analyzing the proposed evolutionary origins of other disease states to that of schizophrenia. To date, several models have been applied. We have tried to conceptualize schizophrenia in a compensatory advantage framework whereby incomplete penetrance of the full disorder, or alternatively, the inheritance of risk alleles insufficient in number to manifest as the classic clinical syndrome, may manifest as a behavioral phenotype with adaptive advantages (eg, creative behavior or novel illuminating ideas). The idea that even full penetrance can also be advantageous has been offered as applied to religious experience and ancient social standing, but is unlikely. Can complex behavioral phenotypes such as schizophrenia, and particularly those that seem purely deleterious, be explained by mechanisms of Darwinian psychiatry? Can models from other disease classes be applied successfully to schizophrenia? Such ideas have generated intense speculation, but often in the absence of testable models. In this article, we will examine some of these proposed ideas and offer suggestions for future research.
Topics: Biological Evolution; Cognition Disorders; Evolution, Molecular; Gene Expression; Genetic Predisposition to Disease; Genotype; Humans; Models, Genetic; Mutation; Penetrance; Phenotype; Psychiatry; Research Design; Schizophrenia; Schizophrenic Psychology; Selection, Genetic
PubMed: 18033774
DOI: 10.1093/schbul/sbm130 -
EMBO Molecular Medicine Nov 2021Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry...
Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p-eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.
Topics: Ataxia; Humans; Nerve Tissue Proteins; Penetrance; Proteins; RNA, Long Noncoding; Spinocerebellar Degenerations; Trinucleotide Repeat Expansion
PubMed: 34632710
DOI: 10.15252/emmm.202114095 -
Current Opinion in Genetics &... Jun 2012The last decade has witnessed an explosion in the identification of genes, mutations in which appear sufficient to cause clinical phenotypes in humans. This is... (Review)
Review
The last decade has witnessed an explosion in the identification of genes, mutations in which appear sufficient to cause clinical phenotypes in humans. This is especially true for disorders of ciliary dysfunction in which an excess of 50 causal loci are now known; this discovery was driven partly by an improved understanding of the protein composition of the cilium and the co-occurrence of clinical phenotypes associated with ciliary dysfunction. Despite this progress, the fundamental challenge of predicting phenotype and or clinical progression based on single locus information remains unsolved. Here, we explore how the combinatorial knowledge of allele quality and quantity, an improved understanding of the biological composition of the primary cilium, and the expanded appreciation of the subcellular roles of this organelle can be synthesized to generate improved models that can explain both causality but also variable penetrance and expressivity.
Topics: Alleles; Cilia; Ciliary Motility Disorders; Gene Frequency; Genetic Association Studies; Genetic Load; Genetic Loci; Genetics, Medical; Genome, Human; Humans; Mutation; Penetrance; Phenotype; Systems Biology
PubMed: 22632799
DOI: 10.1016/j.gde.2012.04.006 -
Pediatrics Jan 2019Genetic data have the potential to impact patient care significantly. In primary care and in the ICU, patients are undergoing genetic testing. Genetics is also...
BACKGROUND
Genetic data have the potential to impact patient care significantly. In primary care and in the ICU, patients are undergoing genetic testing. Genetics is also transforming cancer care and undiagnosed diseases. Optimal personalized medicine relies on the understanding of disease penetrance. In this article, I examine the complexity of penetrance.
METHODS
In this article, I assess how variable penetrance can be seen with many diseases, including those of different modes of inheritance, and how genomic testing is being applied effectively for many diseases. In this article, I also identify challenges in the field, including the interpretation of gene variants.
RESULTS
Using advancing bioinformatics and detailed phenotypic assessment, we can increase the yield of genomic testing, particularly for highly penetrant conditions. The technologies are useful and applicable to different medical situations.
CONCLUSIONS
There are now effective genome diagnostics for many diseases. However, the best personalized application of these data still requires skilled interpretation.
Topics: Computational Biology; Genetic Diseases, Inborn; Genetic Testing; Genetic Variation; Humans; Penetrance; Phenotype; Precision Medicine
PubMed: 30600267
DOI: 10.1542/peds.2018-1099E -
The Israel Medical Association Journal... Dec 2004Melanoma is the leading cause of death from skin tumors worldwide, with an annual increase in incidence over the past decade. The molecular mechanisms involved in... (Review)
Review
Melanoma is the leading cause of death from skin tumors worldwide, with an annual increase in incidence over the past decade. The molecular mechanisms involved in melanoma pathogenesis are beginning to be unraveled. While a family history of melanoma and exposure to ultraviolet irradiation have been known for years as risk factors in melanoma development, the precise genes involved in inherited predisposition were defined only in the past decade. Germline mutations in two genes that play a pivotal role in controlling cell cycle and division--CDKN2A and cyclin-dependent kinase 4 (CDK4)--have been detected in autosomal, dominant, high penetrance familial melanoma cases. In addition to these two highly penetrant genes, germline mutations and polymorphisms in a few low penetrance genes have been reported in familial melanoma cases: melanocortin-1 receptor, epidermal growth factor, glutathione s-transferase M1, cytochrome p450 debrisoquine hydroxylase locus (CYP2D6) and vitamin D receptor.
Topics: Cytochrome P-450 CYP2D6; Epidermal Growth Factor; Genes, p16; Genetic Predisposition to Disease; Glutathione Transferase; Humans; Melanoma; Penetrance; Receptor, Melanocortin, Type 1; Receptors, Calcitriol
PubMed: 15609895
DOI: No ID Found -
Cold Spring Harbor Perspectives in... Nov 2014Age-related macular degeneration (AMD) is a complex disease caused by a combination of genetic and environmental factors. Genome-wide association studies have identified... (Review)
Review
Age-related macular degeneration (AMD) is a complex disease caused by a combination of genetic and environmental factors. Genome-wide association studies have identified several common genetic variants associated with AMD, which together account for 15%-65% of the heritability of AMD. Multiple hypotheses to clarify the unexplained portion of genetic variance have been proposed, such as gene-gene interactions, gene-environment interactions, structural variations, epigenetics, and rare variants. Several studies support a role for rare variants with large effect sizes in the pathogenesis of AMD. In this work, we review the methods that can be used to detect rare variants in common diseases, as well as the recent progress that has been made in the identification of rare variants in AMD. In addition, the relevance of these rare variants for diagnosis, prognosis, and treatment of AMD is highlighted.
Topics: Alleles; Epigenesis, Genetic; Gene-Environment Interaction; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomic Structural Variation; Humans; Macular Degeneration; Penetrance; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 25377141
DOI: 10.1101/cshperspect.a017202 -
Journal of Human Genetics Jul 2024Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing...
BACKGROUND
Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing literature has limited information on clinical traits and penetrance.
METHODS
We identified cases of distal Xq28 duplication (chrX: 154,126,575-154,709,680, GRCh37/hg19) through a review of clinical records and microarray reports from five centers, encompassing both postnatal and prenatal cases, with no prior family knowledge of the duplication.
RESULTS
Our search found 47 cases across 26 families, with duplications ranging from 208 to 935 Kb. In total, 8 out of 26 index cases featured a 200-300 kb partial duplication, mainly from Armenian/Caucasian Jewish backgrounds. Most prenatal cases showed no major fetal ultrasound malformations. Of cases with known inheritance mode (15 out of 26), maternal inheritance was more common (80%). The study identified seven male carriers of the duplication from six unrelated families, indicating partial penetrance in males.
CONCLUSION
Our study provides key insights into distal Xq28 duplication. Most prenatal tests showed no major fetal ultrasound issues. Maternal inheritance was common, with unaffected mothers. In the postnatal group, a balanced gender distribution was observed. Among male family members, two fathers had ADHD, one was healthy, and one brother had mild symptoms, indicating partial penetrance in males.
Topics: Humans; Male; Female; Penetrance; Chromosomes, Human, X; Chromosome Duplication; Child; Adult; Child, Preschool; Adolescent; Pedigree; Infant; Phenotype
PubMed: 38632380
DOI: 10.1038/s10038-024-01252-7