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Disease Models & Mechanisms Feb 2022The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including... (Review)
Review
The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.
Topics: Animals; Costello Syndrome; Failure to Thrive; Humans; Neurofibromatosis 1; Noonan Syndrome; ras Proteins
PubMed: 35178568
DOI: 10.1242/dmm.049107 -
Lancet (London, England) Jan 2013Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital... (Review)
Review
Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.
Topics: Diagnosis, Differential; Humans; Noonan Syndrome; Prognosis
PubMed: 23312968
DOI: 10.1016/S0140-6736(12)61023-X -
Archives of Disease in Childhood Dec 2022Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. The phenotype varies in severity and can involve multiple organ... (Review)
Review
Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. The phenotype varies in severity and can involve multiple organ systems over a patient's lifetime. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. The phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Lack of awareness of NS among HCPs means that some do not recognise the condition, particularly in mildly affected patients and families. Some families do not want to receive a diagnosis that medicalises a condition that may account for family traits (eg, distinctive facial features and short stature), particularly when a child's physical and cognitive development may be satisfactory. As for any condition with lifelong effects on multiple organ systems, a multidisciplinary approach provides the best care. It is proposed that increasing awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and increase the number of NS diagnoses, with the potential to optimise lifelong patient outcomes. Non-specialists do not need to become experts in either diagnosis or treatment; however, early recognition of NS and referral to an appropriate specialist is important.
Topics: Male; Humans; Noonan Syndrome; Phenotype; Heart Diseases
PubMed: 35246453
DOI: 10.1136/archdischild-2021-322858 -
American Journal of Medical Genetics.... Mar 2020Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of... (Review)
Review
Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen-activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype-phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome-specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.
Topics: Abnormalities, Multiple; Failure to Thrive; Heart Defects, Congenital; Humans; Mutation; Noonan Syndrome; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 32022400
DOI: 10.1002/ajmg.c.31765 -
Anales de Pediatria Jul 2020Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other...
Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies». Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.
Topics: Diagnosis, Differential; Genetic Markers; Genotype; Humans; Mitogen-Activated Protein Kinases; Mutation; Noonan Syndrome; Phenotype; Proto-Oncogene Proteins p21(ras)
PubMed: 32493603
DOI: 10.1016/j.anpedi.2020.04.008 -
Genetics in Medicine : Official Journal... Oct 2018To characterize the molecular genetics of autosomal recessive Noonan syndrome.
PURPOSE
To characterize the molecular genetics of autosomal recessive Noonan syndrome.
METHODS
Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.
RESULTS
Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.
CONCLUSION
These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
Topics: Adolescent; Child; Child, Preschool; Exome; Female; Genetic Linkage; Genetic Predisposition to Disease; Genotype; Heterozygote; Humans; Infant; Male; Mutation; Noonan Syndrome; Pedigree; Protein Isoforms; RNA Splicing; Siblings; Transcription Factors
PubMed: 29469822
DOI: 10.1038/gim.2017.249 -
BMC Medical Genomics Jul 2022Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently... (Review)
Review
BACKGROUND
Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1.
CASE PRESENTATION
A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics.
CONCLUSIONS
We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1.
Topics: Adult; Female; Humans; Molecular Biology; Mutation; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Noonan Syndrome; Skin Neoplasms; Transcription Factors; Young Adult
PubMed: 35840934
DOI: 10.1186/s12920-022-01304-x -
BMC Medical Genetics Mar 2020Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein...
BACKGROUND
Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation.
METHODS
Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced.
RESULTS
Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%).
CONCLUSION
The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.
Topics: Adolescent; Adult; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; Family; Female; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Heart Defects, Congenital; Humans; India; Infant; Infant, Newborn; Male; Noonan Syndrome; Phenotype; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Young Adult
PubMed: 32164556
DOI: 10.1186/s12881-020-0986-5 -
Clinical Genetics Jun 2019Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations....
Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
Topics: Adolescent; Alleles; Child; Child, Preschool; Cohort Studies; Exome; Female; Gene Ontology; Genes, Dominant; Genes, Recessive; Heterozygote; Humans; Infant; Male; Mutation; Noonan Syndrome; Pedigree; Phenotype; Transcription Factors
PubMed: 30859559
DOI: 10.1111/cge.13533 -
Heart Failure Clinics Jan 2022RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be... (Review)
Review
RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.
Topics: Cardiomyopathy, Hypertrophic; Genetic Testing; Heart Defects, Congenital; Humans; Noonan Syndrome; Prognosis
PubMed: 34776080
DOI: 10.1016/j.hfc.2021.07.004