The RASopathies are a complex group of conditions regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel (RAS EP) assessed published and other publicly available evidence ...supporting the association of 19 genes with RASopathy conditions. Using the semiquantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, and Noonan‐like syndrome with loose anagen hair.
The curated evidence supporting each gene–disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association's strength was classified as definitive, strong, moderate, limited, disputed, or no evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also disputed the association of two genes for all RASopathy conditions. Overall, our results provide a greater understanding of the different gene–disease relationships within the RASopathies and can help in guiding and directing clinicians, patients, and researchers who are identifying variants in individuals with a suspected RASopathy.
The ClinGen RASopathy Expert Panel assessed the published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions using ClinGen's semiquantitative literature curation method. Our group assessed the evidence implicating each gene's association with Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan‐like syndrome with loose anagen hair. Our results will guide clinicians, patients and researchers in their understanding of the gene‐disease relationships within the RASopathies.
Objective
To investigate the efficacy and outcomes of chromosomal microarray (CMA) in the cytogenomic evaluation of products of conception (POC).
Method
Over a 42‐month period, 323 POC samples were ...tested by CMA. Results were assessed using variables including phenotype, gestational age, results from orthogonal testing, and follow‐up parental analysis.
Results
CMA identified cytogenetic abnormalities in 47.4% of first trimester losses and 10.9% of second and third trimester losses. Chromosomal microarray results specifically from 5 to 7‐week losses showed similar rates of abnormalities (45.6%) compared to those of all first trimester losses combined. CMA and karyotype results were discordant in 20.0% of cases, most likely due to maternal cell overgrowth in culture. The most prevalent abnormalities identified in all losses were autosomal trisomies, followed by triploidy. In 43/323 cases, the observed abnormality suggested a parental aberration that prompted follow‐up studies; two of these cases indeed identified an inherited aberration.
Conclusion
Our findings of specific types of genetic abnormalities and the respective frequencies by gestational age closely align with those of published karyotype studies, supporting the use of routine CMA testing for POCs. CMA outperforms karyotype analysis because it does not require viable, sterile cultures free of maternal admixture or admixture due to multiple gestations. Finally, CMA results can play an important role in identifying increased recurrence risks for some couples.
Key points
What's already known about this topic?
Cytogenetic analysis of products of conception (POC) reveals cytogenetic abnormalities that can explain pregnancy losses and inform recurrence risks.
POC testing recommendations vary by professional society, with only American College of Obstetricians and Gynecologists recommending routine chromosomal microarray (CMA) a not for early losses.
What does this study add?
CMA increased the overall result yield in cases that could not be analyzed by karyotype.
CMA increased the positive yield, including for early losses, compared with that of karyotype analysis.
Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the ...majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.
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•A genome-wide polygenic score can quantify inherited susceptibility to obesity•Polygenic score effect on weight emerges early in life and increases into adulthood•Effect of polygenic score can be similar to a rare, monogenic obesity mutation•High polygenic score is a strong risk factor for severe obesity and associated diseases
A genome-wide polygenic score quantifies inherited susceptibility to obesity, integrating information from 2.1 million common genetic variants to identify adults at risk of severe obesity.
RASopathies include a group of syndromes caused by pathogenic germline variants in RAS‐MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal ...anomalies. Recently, variants in RASopathy‐associated genes have been reported in individuals with apparently nonsyndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy‐associated genes to cardiomyopathy panels, we tested 11 RASopathy‐associated genes by next‐generation sequencing (NGS), including NGS‐based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Disease‐causing variants were identified in 0.6% (four of 692) of individuals with HCM, including three missense variants in the PTPN11, SOS1, and BRAF genes. Overall, 36 variants of uncertain significance (VUSs) were identified, averaging ∼3VUSs/100 cases. This study demonstrates that adding a subset of the RASopathy‐associated genes to cardiomyopathy panels will increase clinical diagnoses without significantly increasing the number of VUSs/case.
To determine the utility of adding RASopathy‐associated genes to cardiomyopathy panels, we tested 11 RASopathy‐associated genes in 1,111 individuals referred to genetic testing for hypertrophic or dilated cardiomyopathy. Disease‐causing variants in PTPN11, SOS1, and BRAF genes were identified in 0.6% (4/692) of individuals with hypertrophic cardiomyopathy, with ∼3 variants of uncertain significance (VUS) per 100 cases. Our results demonstrate that adding RASopathy‐associated genes to cardiomyopathy panels will increase the clinical utility without significantly increasing the number of VUSs per case.
Accurate and consistent variant classification is required for Precision Medicine. But clinical variant classification remains in its infancy. While recent guidelines put forth jointly by the ...American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) for the classification of Mendelian variants has advanced the field, the degree of subjectivity allowed by these guidelines can still lead to inconsistent classification across clinical molecular genetic laboratories. In addition, there are currently no such guidelines for somatic cancer variants, only published institutional practices. Additional variant classification guidelines, including disease- or gene-specific criteria, along with inter-laboratory data sharing is critical for accurate and consistent variant interpretation.
The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, ...accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case‐control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss‐of‐function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio OR = 9.01; confidence interval CI = 4.93–16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss‐of‐function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.
Standardized and accurate variant assessment is essential for effective medical care. To that end, Clinical Genome (ClinGen) Resource clinical domain working groups (CDWGs) are systematically ...reviewing disease-associated genes for sufficient evidence to support disease causality and creating disease-specific specifications of American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines for consistent and accurate variant classification.
The ClinGen RASopathy CDWG established an expert panel to curate gene information and generate gene- and disease-specific specifications to ACMG-AMP variant classification framework. These specifications were tested by classifying 37 exemplar pathogenic variants plus an additional 66 variants in ClinVar distributed across nine RASopathy genes.
RASopathy-related specifications were applied to 16 ACMG-AMP criteria, with 5 also having adjustable strength with availability of additional evidence. Another 5 criteria were deemed not applicable. Key adjustments to minor allele frequency thresholds, multiple de novo occurrence events and/or segregation, and strength adjustments impacted 60% of variant classifications. Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing.
RAS-specific ACMG-AMP specifications optimized the utility of available clinical evidence and Ras/MAPK pathway-specific characteristics to consistently classify RASopathy-associated variants. These specifications highlight how grouping genes by shared features promotes rapid multigenic variant assessment without sacrificing specificity and accuracy.
Objectives
This study characterizes cytogenetic abnormalities with ultrasound findings to refine counseling following negative cell‐free DNA (cfDNA).
Methods
A retrospective cohort of pregnancies ...with chromosome abnormalities and ultrasound findings was examined to determine the residual risk following negative cfDNA. Cytogenetic data was categorized as cfDNA detectable for aneuploidies of chromosomes 13, 18, 21, X, or Y or non‐cfDNA detectable for other chromosome abnormalities. Ultrasound reports were categorized as structural anomaly, nuchal translucency (NT) ≥3.0 mm, or other “soft markers”. Results were compared using chi squared and Fishers exact tests.
Results
Of the 498 fetuses with cytogenetic abnormalities and ultrasound findings, 16.3% (81/498) had non‐cfDNA detectable results. In the first, second, and third trimesters, 12.4% (32/259), 19.5% (42/215), and 29.2% (7/24) had non‐cfDNA detectable results respectively. The first trimester non‐cfDNA detectable results reduced to 7.7% (19/246) if triploidy was detectable by cfDNA testing. For isolated first trimester NT of 3.0–3.49 mm, 15.8% (6/38) had non‐cfDNA detectable results, while for NT ≥3.5 mm, it was 12.3% (20/162). For cystic hygroma, 4.3% (4/94) had non‐cfDNA detectable results.
Conclusions
Counseling for residual risk following cfDNA in the presence of an ultrasound finding is impacted by gestational age, ultrasound finding, and cfDNA detection of triploidy.
What is already known already known about this topic?
Maternal serum screening for aneuploidies has changed since the introduction of cell‐free DNA (cfDNA) in 2011.
Diagnostic testing with chorionic villus sampling or amniocentesis is recommended in the presence of a structural ultrasound finding.
What does this study add?
When ultrasound findings are present, the rate of cytogenetic anomalies not detectible by cfDNA increases with increasing fetal gestational age.
The size of first trimester nuchal translucency is inversely related to the likelihood of cfDNA detected aneuploidy.
16.3% of cytogenetic abnormalities would likely be missed by cfDNA in the presence of an ultrasound finding.
Background
RASopathies are a group of disorders caused by disruptions to the RAS‒MAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically ...present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as Neurofibromatosis‐Noonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management.
Methods
A derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and café‐au‐lait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14‐gene RASopathy‐associated panel.
Results
In the derivation cohort, six (21%) patients had disease‐causing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had disease‐causing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1. Of those with disease‐causing variants, 5/17 only had an NSD diagnosis.
Conclusions
Adding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results.
Adding the NF1 and SPRED1 genes to Noonan spectrum disorder/RASopathy NGS gene panels modestly increases clinical diagnoses without significantly increasing the VUS burden. Since a diagnosis of NF1 or LS would change patient management, the NF1 and SPRED1 genes should be included on all to Noonan spectrum disorder/RASopathy NGS gene panels, including those used prenatally.
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