Accurate estimates of gene penetrance are critical for evaluating disease risk, guiding clinical decision-making, supporting genetic counseling, and advancing research. Multiple methodologies have been developed to estimate penetrance, aiding in the classification of human genetic disorders. Penetrance estimating approaches for rare and low-frequency/common variants may vary. Building on these approaches, we suggest the adoption of quantitative thresholds to categorize variant penetrance as high (≥70%), moderate (30%–70%), or low (<30%). This penetrance stratification may approximately reflect the continuous influence of genetic variants on disease. Traditionally, human diseases have been classified dichotomously as monogenic or polygenic. Based on these models, high-penetrance variants are typically associated with Mendelian disorders, while low-penetrance variants contribute modestly to disease risk. Since the completion of the human genome project, there have been hundreds of thousands of genetic variants identified in the gray zone between monogenic and polygenic variants. To bridge the conceptual gap between monogenic and polygenic disorders, we previously proposed a novel framework termed genetically transitional disease. This concept highlights disorders influenced by genetic variants of low- to moderate-penetrance along with environment and aligns with the ClinGen Working Group's framework on risk alleles and low-penetrance variants. By overcoming the inadequacy and obstacle of a strictly binary classification of genetic disease and moving beyond, the genetically transitional disease model offers a refined and more advantageous approach to capturing genetic nuances and represents a potential paradigm shift in the interpretation of genetic variation, with more important and broader implications for both patient care and research.

BACKGROUND:Yao syndrome (OMIM 617321) is a chronic and recurring inflammatory disease linked to specific variants in the nucleotide-binding oligomerization domain containing protein 2 (NOD2) gene. OBJECTIVE:This study aimed to further dissect the genetic mechanisms of the disease. METHODS:A total of 405 patients suspected of having systemic autoinflammatory diseases were included. Molecular testing was performed using an autoinflammatory disease gene panel to aid diagnosis. To compare the frequencies of commonly encountered individual and combined NOD2 variants, whole genome sequencing data from the All of Us Research Program, consisting of 128,196 participants of European ancestry, was interrogated. RESULTS:Commonly encountered NOD2 variants and combinations were compared to the All of Us Research Program genomic data. We found that NOD2 variant IVS8 + 158 (JW1) was significantly more prevalent in the patient population (odds ratio [OR] = 1.32, P = .006). Similarly, NOD2 variants p.Leu1007Profs∗2 and p.Arg703Cys were significantly higher in the patient population (OR = 1.61, P = .018; OR = 2.66, P = .004, respectively). Linkage disequilibrium analysis demonstrated a haplotype configuration for IVS8 + 158 and p.Arg702Trp or IVS8 + 158 (JW1) and p.Leu1007Profs∗2. Additionally, NOD2 IVS8 + 158 (JW1) and p.Val955Ile was found to be significantly more frequent in the patient group (OR = 1.63, P = .038). These findings confirm and further expand the association of these individual and combined NOD2 variants with Yao syndrome. CONCLUSION:This large case-control study of population genetics provides valuable insights into the genetic mechanisms of Yao syndrome and has important implications for ordering genetic tests, interpretation of the results, genomic diagnosis, and genetic counseling.

Genetically transitional disease (GTD) is emerging as a new concept in genomic medicine to straddle between the traditional binary classification of monogenic and polygenic disease. Genetic testing result reports in molecular laboratories have been predicated on the monogenic disease model, which focuses on pathogenic and likely pathogenic variants. While variants of uncertain significance (VUS) are reported by laboratories, there are challenges with regard to their clinical application so that these variants are often dismissed by ordering physicians. Unlike Mendelian disorders, where genetic variants are of high penetrance and highly probabilistic, the GTD concept is employed to highlight the impact of low-to-moderate effect gene variants whose influence on disease is modified by the genetic background. The GTD concept may explain health conditions associated with variants that are necessary but not sufficient for pathogenesis, lying in the mid gray zone between Mendelian and polygenic diseases. Although VUSs may not reach the level of pathogenicity based on American College of Medical Genetics and Genomics guidelines, they could be provisionally classified as GTD-associated variants to annotate and interpret the relationship between VUS and human genetic disease. The appropriate implementation of the GTD concept could impact patient care and research by focusing attention on the individual variability of responses in various diseases.

In genomic medicine, the concept of genetically transitional disease (GTD) refers to cases in which gene mutation is necessary but not sufficient to cause disease. In this Perspective, we apply this novel concept to rheumatic diseases, which have been linked to hundreds of genetic variants via association studies. These variants are in the 'grey zone' between monogenic variants with large effect sizes and common susceptibility alleles with small effect sizes. Among genes associated with rare autoinflammatory diseases, many low-frequency and/or low-penetrance variants are known to increase susceptibility to systemic inflammation. In autoimmune diseases, hundreds of HLA and non-HLA genetic variants have been revealed to be modest- to moderate-risk alleles. These diseases can be reclassified as GTDs. The same concept could apply to many other human diseases. GTD could improve the reporting of genetic testing results, diagnostic yields, genetic counselling and selection of therapy, as well as facilitating research using a novel approach to human genetic diseases.

ObjectiveYao syndrome (YAOS) is formerly called nucleotide-binding oligomerization domain containing 2 (NOD2)-associated autoinflammatory disease.We report a large cohort of YAOS.MethodsWe conducted a retrospective analysis of a cohort of adult patients with systemic autoinflammatory diseases (SAIDs). All patients underwent testing for a periodic fever syndrome gene panel.ResultsA total of 194 patients carried NOD2 variants, 152 patients were diagnosed with YAOS, and 42 had mixed autoinflammatory diseases with combined variants in NOD2 and other SAID-associated genes. Demographic, clinical and molecular data were summaried. In sub-group analysis of the 194 patients, individual patients were often identified to carry two or more variants that usually included IVS8 + 158/R702W, IVS8 + 158/L1007fs, IVS8 + 158/V955I, IVS8 + 158/other, or NOD2/variants in other SAID genes. Ninety-nine patients carried single variants. Taken together, these variants contribute to the disease in combination or individually.ConclusionThis largest cohort has provided comprehensive clinical and genotyping data in YAOS. Variants in the NOD2 gene can give rise to a spectrum from inflammatory bowel disease to autoinflammatory disease.This report further raises awareness of the underdiagnosed disease in the medical community.

Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.

ObjectivesCryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance. Both diseases are rare, primarily reported in the pediatric population, and are thought to be phenotypically indistinguishable. We provide the largest cohort of adult-onset patients and compared these diseases and the gene variant frequency to population controls.MethodsA cohort of adult patients with AIDs were retrospectively studied. All underwent molecular testing for periodic fever syndrome gene panels after extensive and negative workups for systemic autoimmune and other related diseases. Patients were divided into Group 1- NLRP3-AID patients with NLRP3 variants (N=15), Group 2- NLRP12-AID with NLRP12 variants (N=14) and Group 3- both NLRP3 and NLRP12 (N=9) variants. Exome sequence data of two large control populations including the ARIC study were used to compare gene variant distribution and frequency.ResultsAll 38 patients were Caucasian with women accounting for 82%. Median age at diagnosis was 41 ± 23 years and the disease duration at diagnosis was 14 ± 13 years. We identified statistically significant differences between the groups, notably that gastrointestinal symptoms as well as evaluations for same were significantly more frequent in patients with NLRP12 variants, and headaches/dizziness were less common among the NLRP12 patients. Livedo reticularis was noted in four patients, exclusively among NLRP12 carriers. Over 50% of patients in Groups 1 and 2 carry low-frequency disease-associated variants, while the remaining carry rare variants. We unprecedently identified digenic variants, i.e., the coexistence of NLRP3 and NLRP12, which were either both low frequency or low frequency/rare. Allele frequencies of all variants identified in our cohort were either absent or significantly lower in the control populations, further strengthening the evidence of susceptibility of these variants to SAID phenotypes.ConclusionOur comparative study shows that both NLRP3-AID and NLRP12-AID share similar clinical phenotypes, yet there are significant differences between them with regard to gastrointestinal and neurological symptoms. A spectrum of high to low genetic variations in both genes can contribute to SAID individually or in combination.

NOD-like receptors (NLRs) are intracellular sensors associated with systemic autoinflammatory diseases (SAIDs). We investigated the largest monocentric cohort of patients with adult-onset SAIDs for coinheritance of low frequency and rare mutations in NOD2 and other autoinflammatory genes. Sixty-three patients underwent molecular testing for SAID gene panels after extensive clinical workups. Whole exome sequencing data from the large Atherosclerosis Risk in Communities (ARIC) study of individuals of European-American ancestry were used as control. Of 63 patients, 44 (69.8%) were found to carry combined gene variants in NOD2 and another gene (Group 1), and 19 (30.2%) were carriers only for NOD2 variants (Group 2). The genetic variant combinations in SAID patients were digenic in 66% (NOD2/MEFV, NOD2/NLRP12, NOD2/NLRP3, and NOD2/TNFRSF1A) and oligogenic in 34% of cases. These variant combinations were either absent or significantly less frequent in the control population. By phenotype-genotype correlation, approximately 40% of patients met diagnostic criteria for a specific SAID, and 60% had mixed diagnoses. There were no statistically significant differences in clinical manifestations between the two patient groups except for chest pain. Due to overlapping phenotypes and mixed genotypes, we have suggested a new term, “Mixed NLR-associated Autoinflammatory Disease “, to describe this disease scenario. Gene variant combinations are significant in patients with SAIDs primarily presenting with mixed clinical phenotypes. Our data support the proposition that immunological disease expression is modified by genetic background and environmental exposure. We provide a preliminary framework in diagnosis, management, and interpretation of the clinical scenario.

Traditional classification of genetic diseases as monogenic and polygenic has lagged far behind scientific progress. In this opinion article, we propose and define a new terminology, genetically transitional disease (GTD), referring to cases where a large-effect mutation is necessary, but not sufficient, to cause disease. This leads to a working disease nosology based on gradients of four types of genetic architecture: monogenic, polygenic, GTD, and mixed. We present four scenarios under which GTD may occur; namely, subsets of traditionally Mendelian disease, modifiable Tier 1 monogenic conditions, variable penetrance, and situations where a genetic mutational spectrum produces qualitatively diver-gent pathologies. The implications of the new nosology in precision medicine are discussed, in which therapeutic options may target the molecular cause or the disease phenotype.

Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of amyloid fibrils in the myocardium leads to cardiac amyloidosis, which is often overlooked as a cause of diastolic heart failure. Although cardiac amyloidosis was previously believed to have a poor prognosis, recent advances in diagnosis and treatment have emphasized the importance of early recognition and changed management of this condition. This article provides an overview of cardiac amyloidosis and summarizes current screening, diagnosis, evaluation, and treatment options.

To the Editor: Yao syndrome (YAOS, Online Mendelian Inheritance in Man [OMIM] 617321) is formerly termed nucleotide-binding oligomerization domain 2(NOD2)-associated autoinflammatory disease. It is characterized by periodic fever, dermatitis, arthritis, swelling of the distal extremities, gastrointestinal and sicca-like symptoms, and eyelid swelling. Specific NOD2 variants increase susceptibility to the disease.1-3 Herein, we report a new genetic marker for YAOS.

Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of amyloid fibrils in the myocardium leads to cardiac amyloidosis, which is often overlooked as a cause of diastolic heart failure. Although cardiac amyloidosis was previously believed to have a poor prognosis, recent advances in diagnosis and treatment have emphasized the importance of early recognition and changed management of this condition. This article provides an overview of cardiac amyloidosis and summarizes current screening, diagnosis, evaluation, and treatment options.

Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of amyloid fibrils in the myocardium leads to cardiac amyloidosis, which is often overlooked as a cause of diastolic heart failure. Although cardiac amyloidosis was previously believed to have a poor prognosis, recent advances in diagnosis and treatment have emphasized the importance of early recognition and changed management of this condition. This article provides an overview of cardiac amyloidosis and summarizes current screening, diagnosis, evaluation, and treatment options.

Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of amyloid fibrils in the myocardium leads to cardiac amyloidosis, which is often overlooked as a cause of diastolic heart failure. Although cardiac amyloidosis was previously believed to have a poor prognosis, recent advances in diagnosis and treatment have emphasized the importance of early recognition and changed management of this condition. This article provides an overview of cardiac amyloidosis and summarizes current screening, diagnosis, evaluation, and treatment options.

Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of amyloid fibrils in the myocardium leads to cardiac amyloidosis, which is often overlooked as a cause of diastolic heart failure. Although cardiac amyloidosis was previously believed to have a poor prognosis, recent advances in diagnosis and treatment have emphasized the importance of early recognition and changed management of this condition. This article provides an overview of cardiac amyloidosis and summarizes current screening, diagnosis, evaluation, and treatment options.

Background Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years. Methods Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004. Results In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen–inotersen) and 39 switched from placebo to inotersen (placebo–inotersen). The placebo–inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen–inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo–inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study. Conclusion Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Hereditary transthyretin amyloidosis (hATTR), a progressive, debilitating, and ultimately fatal disease, causes multisystem dysfunction. We report long-term efficacy and safety for inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production.