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2.
Am J Med Genet A ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31368252

RESUMO

Adams-Oliver syndrome (AOS) is a rare congenital disease characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It shows significant genetic heterogeneity and can be transmitted by autosomal dominant or recessive inheritance. Recessive inheritance is associated with mutations of DOCK6 or EOGT; however, only few cases have been published so far. We present two families with EOGT-associated AOS. Due to pseudodominance in one family, the recognition of the recessive inheritance pattern was difficult. We identified two novel AOS-causing mutations (c.404G>A/p.Cys135Tyr and c.311+1G>T). The phenotype in the presented families was dominated by large ACC, whereas TTLD were mostly subtle or even absent and no major malformations occured. Our observations along with the previously published cases indicate that the two types of recessive AOS (EOGT- vs. DOCK6-associated) differ significanty regarding the frequency of neurologic or ocular deficits.

4.
Hum Mol Genet ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31108500

RESUMO

The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

5.
Am J Hum Genet ; 104(6): 1223-1232, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130282

RESUMO

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

6.
Genes Chromosomes Cancer ; 58(10): 723-730, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31102422

RESUMO

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10-3 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

7.
Mol Genet Genomic Med ; 7(5): e625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891959

RESUMO

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , GTP Fosfo-Hidrolases/genética , Humanos , Lipomatose/patologia , Proteínas de Membrana/genética , Mosaicismo , Síndromes Neurocutâneas/patologia , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
Eur J Hum Genet ; 27(7): 1061-1071, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30809043

RESUMO

Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.

9.
Am J Med Genet A ; 179(5): 832-836, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30803155

RESUMO

Interstitial deletions within the chromosomal region 2q24.2 have already been linked to intellectual disability (ID) in the past. In most cases the described patients showed a syndromic form of ID associated with large deletions containing multiple genes. Here we describe a family with two siblings with mild non-syndromic ID. They shared the same 564 kb deletion in the chromosomal region 2q24.2 containing only the TANK gene, which was inherited from the similarly affected father, thus suggesting haploinsufficiency of TANK as a novel cause of non-syndromic ID. TANK encodes the TRAF family member-associated NF-kappa-B activator (OMIM #603893), which is expressed in many tissues. It functions as an adapter protein that interacts with the NF-kappa-B pathway and SOX11, an essential transcription factor in regeneration, survival and differentiation of the neuronal system. TANK has not been linked to ID or other human diseases before. To further elucidate the role of TANK in non-syndromic ID, we screened a cohort of 288 TANK deletion negative non-syndromic mental retardation patients for TANK mutations without identifying any pathogenic variant.

10.
Nat Med ; 25(1): 60-64, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617323

RESUMO

Syndromic genetic conditions, in aggregate, affect 8% of the population1. Many syndromes have recognizable facial features2 that are highly informative to clinical geneticists3-5. Recent studies show that facial analysis technologies measured up to the capabilities of expert clinicians in syndrome identification6-9. However, these technologies identified only a few disease phenotypes, limiting their role in clinical settings, where hundreds of diagnoses must be considered. Here we present a facial image analysis framework, DeepGestalt, using computer vision and deep-learning algorithms, that quantifies similarities to hundreds of syndromes. DeepGestalt outperformed clinicians in three initial experiments, two with the goal of distinguishing subjects with a target syndrome from other syndromes, and one of separating different genetic subtypes in Noonan syndrome. On the final experiment reflecting a real clinical setting problem, DeepGestalt achieved 91% top-10 accuracy in identifying the correct syndrome on 502 different images. The model was trained on a dataset of over 17,000 images representing more than 200 syndromes, curated through a community-driven phenotyping platform. DeepGestalt potentially adds considerable value to phenotypic evaluations in clinical genetics, genetic testing, research and precision medicine.


Assuntos
Aprendizado Profundo , Facies , Doenças Genéticas Inatas/diagnóstico , Algoritmos , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Fenótipo , Síndrome
11.
Nephron ; 141(3): 156-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30557881

RESUMO

AIM: Aim of this study was to investigate the association of genetic variants of functional polymorphisms of matrix metalloproteinase and Cubilin (CUBN) with diabetic nephropathy (DN), end-stage renal disease (ESRD), and risk of cardiovascular disease (CVD) in Caucasian type 2 diabetes (T2D) patients. METHODS: 472 T2D-patients were genotyped for 3 single-nucleotide polymorphisms (SNPs; MMP-2 [rs2285053], MMP-9 [rs17576] and CUBN [rs1801239]). Genotyping was carried out by allelic discrimination using TaqMan SNP-genotyping-assay. RESULTS: MMP-9 (Gln279Arg) AA-genotype (OR 0.17 [0.04-0.62, p = 0.008]) and the time elapsed since diagnosis of T2D without onset of proteinuria (OR 0.87 [0.79-0.97, p = 0.008]) were found to be independently associated with reduced risk of susceptibility to DN. On the contrary higher stages of chronic kidney disease (OR 1.93 [1.15-3.23], p = 0.012) and the presence of MMP-9 GG-genotype were independently associated with DN (OR 6.07 [1.60-22.99], p = 0.008). The CUBN CC or C-risk-allele of rs1801239 was associated with ESRD (OR 2.04 [1.07-3.87], p = 0.03) and peripheral artery disease (OR 2.08 [1.12-3.88], p = 0.021). We could not find an association with MMP-2, MMP-9, or CUBN with CVD in a composite clinical endpoint model. CONCLUSIONS: This study highlights that MMP-9 or CUBN-SNPs may exert effects on risk of susceptibility to DN or ESRD. We provide novel evidence on genetic susceptibility for macroangiopathy in patients with a missense variant of CUBN (Ile2984Val) in patients with T2D.

13.
Cell Commun Signal ; 16(1): 96, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518391

RESUMO

BACKGROUND: Human pluripotent stem cells (PSCs) open new windows for basic research and regenerative medicine due to their remarkable properties, i.e. their ability to self-renew indefinitely and being pluripotent. There are different, conflicting data related to the role of basic fibroblast growth factor (bFGF) in intracellular signal transduction and the regulation of pluripotency of PSCs. Here, we investigated the effect of bFGF and its downstream pathways in pluripotent vs. differentiated human induced (hi) PSCs. METHODS: bFGF downstream signaling pathways were investigated in long-term culture of hiPSCs from pluripotent to differentiated state (withdrawing bFGF) using immunoblotting, immunocytochemistry and qPCR. Subcellular distribution of signaling components were investigated by simple fractionation and immunoblotting upon bFGF stimulation. Finally, RAS activity and RAS isoforms were studied using RAS assays both after short- and long-term culture in response to bFGF stimulation. RESULTS: Our results revealed that hiPSCs were differentiated into the ectoderm lineage upon withdrawing bFGF as an essential pluripotency mediator. Pluripotency markers OCT4, SOX2 and NANOG were downregulated, following a drastic decrease in MAPK pathway activity levels. Notably, a remarkable increase in phosphorylation levels of p38 and JAK/STAT3 was observed in differentiated hiPSCs, while the PI3K/AKT and JNK pathways remained active during differentiation. Our data further indicate that among the RAS paralogs, NRAS predominantly activates the MAPK pathway in hiPSCs. CONCLUSION: Collectively, the MAPK pathway appears to be the prime signaling pathway downstream of bFGF for maintaining pluripotency in hiPSCs and among the MAPK pathways, the activity of NRAS-RAF-MEK-ERK is decreased during differentiation, whereas p38 is activated and JNK remains constant.

14.
Orphanet J Rare Dis ; 13(1): 226, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558655

RESUMO

BACKGROUND: Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and microcephaly with central nervous system anomalies. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogenous group of disorders. Recently, it has been reported that mutations in KEOPS-encoding genes, including the OSGEP gene, were responsible for GAMOS. RESULTS: Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age. We reviewed their clinical manifestations, the prenatal and postnatal presentations and ultrasound findings, results of imaging studies, associated anomalies, and outcome on follow-up. All individuals were found to have an "aged face" comprising peculiar facial dysmorphisms. Arachnodactyly or camptodactyly were noted in all patients. Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures. Brain imaging studies all showed pachygyria and hypomyelination. All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment. Prenatal ultrasound findings included microcephaly, intrauterine growth restriction, and oligohydramnios. Fetal MRI in 2 patients confirmed the gyral and myelin abnormalities. CONCLUSIONS: Our study suggests that a careful review of the facial features can provide useful clues for an early and accurate diagnosis. Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis.


Assuntos
Hérnia Hiatal/genética , Metaloendopeptidases/genética , Microcefalia/genética , Nefrose/genética , Aracnodactilia/genética , Feminino , Humanos , Lisencefalia/genética , Masculino , Mutação/genética , Síndrome Nefrótica/genética , Diagnóstico Pré-Natal , Estudos Retrospectivos , Taiwan
15.
Eur J Med Genet ; 2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30590172

RESUMO

Roberts/SC phocomelia syndrome (RBS/SC) is a rare autosomal recessive inherited condition characterized by prenatal-onset growth retardation, craniofacial anomalies, and symmetrical limb reduction defects. Here, we present two affected siblings with RBS/SC who have consanguineous parents. Both patients had intrauterine growth retardation; similar facial findings, including arched eyebrows, epicanthic folds, posteriorly angulated ears, and retrognathia; and hypopigmented patches on their skin. However, despite these common findings, the extremity involvement was different between the patients. The more severely affected boy had hypoplasia of the tibia and symmetrical agenesis of the radius, ulna, proximal carpal bones, and fibula. The slightly affected girl presented with mild symmetrical mesomelic shortening. The cytogenetic analysis showed aneuploidies at varying rates concerning different chromosomes in the analyses of different culture materials. As a remarkable finding in the cytogenetic studies, chromosome analysis of fibroblast cultures obtained from the hypopigmented skin region showed a much higher frequency of aneuploidy, especially trisomy 7, than normopigmented skin fibroblasts and lymphocyte cultures for both patients, which was also proven ex vivo by qPCR analyses from uncultured skin tissues. In the subsequent ESCO2 gene sequence analysis, both patients were found to be homozygous for the mutation c.1111dupA (p.Thr371Asnfs*32; NM_001017420.2), which is known to be pathogenic. In the literature search, only two RBS/SC patient reports with hypopigmented skin patches could be found. In addition, the presence of pigmentation defects in the embryo was reported in some different animal models for RBS/SC. When the literature review and study are evaluated together, hypopigmented patches can be considered as a rare finding for RBS/SC. It can be suggested that somatic aneuploidies seen in the natural course of the disease, especially aneuploidy of chromosome 7, which has many genes associated with pigmentation, may be responsible for the hypopigmentation patches.

16.
Mol Nutr Food Res ; : e1800076, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30378765

RESUMO

SCOPE: Diet is amongst the most crucial factors contributing to the multistep process of carcinogenesis. The role of exogenous microRNAs (miRNAs) is still debatable. In this proof-of-principle work, the presence of miRNAs in a variety of foods, its stability to processing, and detectability in GI mucosa and feces are studied and the effect of short-term diet on human- or plant-derived miRNAs in feces and blood is examined. METHODS AND RESULTS: Animal and plant miRNAs are detected in all foods irrespective of processing. Animal-derived foods showed the highest miRNA level and the lowest is found in cheese and milk. The impact of the short-term vegetarian or meat-rich diet on blood and feces miRNA is evaluated in healthy subjects using qPCR and Affymetrix profiling. Diet is not associated with changes in ultraconserved miRNAs. However, a vegetarian diet is associated with an increase of miR-168 in feces but not in blood. Overall, plant miR-168 is detectable in normal GI mucosa and in colorectal cancer. CONCLUSIONS: Food provides a great source of miRNAs and diet may be associated with changes in xenomiRs. Plant-derived miR-168 is ubiquitously present in feces, normal mucosa, and cancer. Further studies are needed to evaluate the functional interaction between diet-derived miRNAs and GI tract.

17.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

18.
Hum Mol Genet ; 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30481304

RESUMO

Noonan syndrome (NS), the most common RASopathy, is caused by mutations affecting signaling through RAS and the MAPK cascade. Recently, genome scanning has discovered novel genes implicated in NS, whose function in RAS-MAPK signaling remains obscure, suggesting the existence of unrecognized circuits contributing to signal modulation in this pathway. Among these genes, LZTR1 encodes a functionally poorly characterized member of the BTB/POZ protein superfamily. Two classes of germline LZTR1 mutations underlie dominant and recessive forms of NS, while constitutional monoallelic, mostly inactivating, mutations in the same gene cause schwannomatosis, a cancer-prone disorder clinically distinct from NS. Here we show that dominant NS-causing LZTR1 mutations do not affect significantly protein stability and subcellular localization. We provide the first evidence that these mutations, but not the missense changes occurring as biallelic mutations in recessive NS, enhance stimulus-dependent RAS-MAPK signaling, which is triggered, at least in part, by an increased RAS protein pool. Moreover, we document that dominant NS-causing mutations do not perturb binding of LZTR1 to CUL3, a scaffold coordinating the assembly of a multimeric complex catalyzing protein ubiquitination, but are predicted to affect the surface of the Kelch domain mediating substrate binding to the complex. Collectively, our data suggest a model in which LZTR1 contributes to the ubiquitination of protein(s) functioning as positive modulator(s) of the RAS-MAPK signaling pathway. In this model, LZTR1 mutations are predicted to variably impair binding of these substrates to the multi-component ligase complex and their efficient ubiquitination and degradation, resulting in MAPK signaling upregulation.

20.
Hum Mutat ; 39(11): 1485-1493, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30311384

RESUMO

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.

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