Investigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders.

Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10-7). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Germline predisposition to myeloid neoplasms: Characteristics and management of high versus variable penetrance disorders.

Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients.

How do stochastic processes and genetic threshold effects explain incomplete penetrance and inform causal disease mechanisms?

Incomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the combination of incomplete penetrance for each of multiple independent clinical features. Within genetically identical individuals, such as isogenic model organisms, stochastic variation at molecular and cellular levels is the primary cause of incomplete penetrance according to a genetic threshold model. By defining specific probability distributions of causal biological readouts and genetic liability values, stochasticity and incomplete penetrance provide information about threshold values in biological systems. Ascertainment of threshold values has been achieved by simultaneous scoring of relatively simple phenotypes and quantitation of molecular readouts at the level of single cells. However, this is much more challenging for complex morphological phenotypes using experimental and reductionist approaches alone, where cause and effect are separated temporally and across multiple biological modes and scales. Here I consider how causal inference, which integrates observational data with high confidence causal models, might be used to quantify the relative contribution of different sources of stochastic variation to phenotypic diversity. Collectively, these approaches could inform disease mechanisms, improve predictions of clinical outcomes and prioritize gene therapy targets across modes and scales of gene function. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.

Renal Hypodysplasia/Aplasia 3 Caused by a Rare Variant of GREB1L With Incomplete Penetrance in a Chinese Family.

Renal agenesis represents the most severe form of congenital anomalies of the kidney and urinary tract. Bilateral renal agenesis is almost invariably fatal at birth and has high genetic heterogeneity. Here we report on a Chinese family with two pregnancies affected by a prenatal form of bilateral renal agenesis. Trio-WES was conducted to explore the underlying genetic cause and identified a novel nonsense variant (c .2621G>A: p. Trp874Ter) in the GREB1L gene. Based on previous research, pathogenic mutations in GREB1L can cause renal hypodysplasia/aplasia-3 (RHDA3) with autosomal dominant inheritance. Sanger sequencing performed on the family members revealed that the variant was vertically transmitted from the maternal grandfather through the unaffected mother to the two affected fetuses, fully demonstrating the incomplete dominance of the disease. Our study extends the mutational spectrum associated with RHDA3 and contributes to a more general understanding for the complex genetic inheritance of GREB1L.

Data from electronic healthcare records expand our understanding of X-linked genetic diseases.

Disease specific cohort studies have reported details on X linked (XL) disorders affecting females. We investigated the spectrum and penetrance of XL disorders seen in electronic health records (EHR). We generated a cohort of individuals diagnosed with XL disorders at Vanderbilt University Medical Center over 20 years. Our cohort included 477 males and 203 females diagnosed with 108 different XL genetic disorders. We found large differences between the female/male (F/M) ratios for various XL disorders regardless of their OMIM annotated mode of inheritance. We identified four XL recessive disorders affecting women previously only described in men. Biomarkers for XL disease had unique gender-specific patterns differing between modes of inheritance. EHRs provide large cohorts of XL genetic disorders that give new insights compared to the literature. Differences in the F/M ratios and biomarkers of XL disorders observed likely result from disease specific and sex dependent penetrance. We conclude that observed gender ratios associated with specific XL disorders may be more useful than those predicted by Mendelian genetics provided by OMIM. Our findings of a gender specific penetrance and severity for XL disorders show unexpected differences from Mendelian predictions. Further work is required to validate our findings in larger combined EHR cohorts.

Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Women's attitudes towards disclosure of genetic information in pregnancy with varying levels of penetrance.

BACKGROUND: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. METHODS: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. RESULTS: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). CONCLUSION: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests.

Affinity-optimizing enhancer variants disrupt development.

Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.

TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance.

Titin (TTN) is one of the largest and most complex proteins expressed in humans, and truncation variants are the most prevalent genetic lesion identified in individuals with dilated cardiomyopathy (DCM) or other disorders of impaired cardiac contractility. Two reports in this issue of the JCI shed light on a potential mechanism involving truncated TTN sarcomere integration and the potential for disruption of sarcomere structural integrity. Kellermayer, Tordai, and colleagues confirmed the presence of truncated TTN protein in human DCM samples. McAfee and authors developed a patient-specific TTN antibody to study truncated TTN subcellular localization and to explore its functional consequences. A "poison peptide" mechanism emerges that inspires alternative therapeutic approaches while opening new lines for inquiry, such as the role of haploinsufficiency of full-length TTN protein, mechanisms explaining sarcomere dysfunction, and explanations for variable penetrance.

Inborn errors of immunity: an expanding universe of disease and genetic architecture.

Inborn errors of immunity (IEIs) are generally considered to be rare monogenic disorders of the immune system that cause immunodeficiency, autoinflammation, autoimmunity, allergy and/or cancer. Here, we discuss evidence that IEIs need not be rare disorders or exclusively affect the immune system. Namely, an increasing number of patients with IEIs present with severe dysregulations of the central nervous, digestive, renal or pulmonary systems. Current challenges in the diagnosis of IEIs that result from the segregated practice of specialized medicine could thus be mitigated, in part, by immunogenetic approaches. Starting with a brief historical overview of IEIs, we then discuss the technological advances that are facilitating the immunogenetic study of IEIs, progress in understanding disease penetrance in IEIs, the expanding universe of IEIs affecting distal organ systems and the future of genetic, biochemical and medical discoveries in this field.

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.

Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.

Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.

Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance.

BACKGROUND: Mutations in PTH1R are associated with Jansen-type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation. METHODS: The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software. RESULTS: High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic. CONCLUSIONS: We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results From a Dutch Multicenter Cohort Study.

BACKGROUND: MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). Screening of relatives of patients with genetic cardiomyopathy is recommended from 10 to 12 years of age onward, irrespective of the affected gene. OBJECTIVES: This study sought to study the penetrance and prognosis of MYH7 variant-associated cardiomyopathies. METHODS: In this multicenter cohort study, penetrance and major cardiomyopathy-related events (MCEs) were assessed in carriers of (likely) pathogenic MYH7 variants by using Kaplan-Meier curves and log-rank tests. Prognostic factors were evaluated using Cox regression with time-dependent coefficients. RESULTS: In total, 581 subjects (30.1% index patients, 48.4% male, median age 37.0 years [IQR: 19.5-50.2 years]) were included. HCM was diagnosed in 226 subjects, NCCM in 70, and DCM in 55. Early penetrance and MCEs (age <12 years) were common among NCCM-associated variant carriers (21.2% and 12.0%, respectively) and DCM-associated variant carriers (15.3% and 10.0%, respectively), compared with HCM-associated variant carriers (2.9% and 2.1%, respectively). Penetrance was significantly increased in carriers of converter region variants (adjusted HR: 1.87; 95% CI: 1.15-3.04; P = 0.012) and at age ≤1 year in NCCM-associated or DCM-associated variant carriers (adjusted HR: 21.17; 95% CI: 4.81-93.20; P < 0.001) and subjects with a family history of early MCEs (adjusted HR: 2.45; 95% CI: 1.09-5.50; P = 0.030). The risk of MCE was increased in subjects with a family history of early MCEs (adjusted HR: 1.82; 95% CI: 1.15-2.87; P = 0.010) and at age ≤5 years in NCCM-associated or DCM-associated variant carriers (adjusted HR: 38.82; 95% CI: 5.16-291.88; P < 0.001). CONCLUSIONS: MYH7 variants can cause cardiomyopathies and MCEs at a young age. Screening at younger ages may be warranted, particularly in carriers of NCCM- or DCM-associated variants and/or with a family history of MCEs at <12 years.

Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers.

Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.

Reduced penetrance of gene variants causing amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72, SOD1, TARDBP and FUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level. OBJECTIVE: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis. METHODS: Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for C9orf72 were obtained from the published literature. RESULTS: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for C9orf72 (95% CI (20.9 to 53.2)), 54% for SOD1 (95% CI (32.7 to 88.6)), 38% for TARDBP (95% CI (21.1 to 69.8)) and 19% for FUS (95% CI (13.0 to 28.4)). CONCLUSION: Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.

A theoretical perspective on Waddington's genetic assimilation experiments.

Genetic assimilation is the process by which a phenotype that is initially induced by an environmental stimulus becomes stably inherited in the absence of the stimulus after a few generations of selection. While the concept has attracted much debate after being introduced by C. H. Waddington 70 y ago, there have been few experiments to quantitatively characterize the phenomenon. Here, we revisit and organize the results of Waddington's original experiments and follow-up studies that attempted to replicate his results. We then present a theoretical model to illustrate the process of genetic assimilation and highlight several aspects that we think require further quantitative studies, including the gradual increase of penetrance, the statistics of delay in assimilation, and the frequency of unviability during selection. Our model captures Waddington's picture of developmental paths in a canalized landscape using a stochastic dynamical system with alternative trajectories that can be controlled by either external signals or internal variables. It also reconciles two descriptions of the phenomenon-Waddington's, expressed in terms of an individual organism's developmental paths, and that of Bateman in terms of the population distribution crossing a hypothetical threshold. Our results provide theoretical insight into the concepts of canalization, phenotypic plasticity, and genetic assimilation.

Polygenic risk alters the penetrance of monogenic kidney disease.

Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.