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Published in final edited form as: Curr Opin Cell Biol. 2018 Jul 11;55:42–51. doi: 10.1016/j.ceb.2018.06.007

RAS GTPase-dependent pathways in developmental diseases: old guys, new lads, and current challenges

Xosé R Bustelo 1,2,3,✉, Piero Crespo 4,5, Isabel Fernández-Pisonero 1,2,3, Sonia Rodríguez-Fdez 1,2
PMCID: PMC7615762  EMSID: EMS194754  PMID: 30007125

Abstract

Deregulated RAS signaling is associated with increasing numbers of congenital diseases usually referred to as RASopathies. The spectrum of genes and mutant alleles causing these diseases has been significantly expanded in recent years. This progress has triggered new challenges, including the origin and subsequent selection of the mutations driving these diseases, the specific pathobiological programs triggered by those mutations, the type of correlations that exist between the genotype and the clinical features of patients, and the ancillary genetic factors that influence the severity of the disease in patients. These issues also directly impinge on the feasibility of using RAS pathway drugs to treat RASopathy patients. Here, we will review the main developments and pending challenges in this research topic.

Introduction

RAS proteins are molecular switches that control life-essential processes linked to cell differentiation, proliferation, andcell-type specific responses duringembryogenesis and the postnatal period. Due to this, their biosynthesis, activation, and the assembly of downstream pathways are tightly controlled in order to ensure proper signaling outputs both in time and space during cell stimulation conditions (Box 1) [1]. However, when this regulatory system goes awry, the toll paid is the development of diseases such as cancer and congenital RASopathies (Box 1 and Figure 1). In this work, we will summarize recent results and current challenges regarding the implication of RAS signaling elements in both germline and mosaic RASopathies. Readers will find additional information not covered by our review on the history, clinical features, and animal model-generated biological data of these diseases else-where [2,3].

Box 1. Depiction of the RAS signaling pathway.

Upon synthesis in the cytosol, RAS family proteins undergo a stepwise maturation at the endoplasmic reticulum and Golgi complex that includes the farnesylation of the C-terminal CAAX box, the removal of the C-terminal tripeptide, and the methylation of the α-carbonyl group of the newly exposed C-terminal prenylated cysteine residue (Step a). Depending on the GTPase, these maturation steps can be different. For example, some GTPases can indistinctly undergo farnesylation and geranylgeranylation (e.g. KRAS). Other GTPases can also scape this maturation step since they lack the C-terminal CAAX box present in the rest of family members (e.g. RIT1). To become active, RAS proteins have to undergo the exchange of the bound GDP by GTP. This process is catalyzed by RAS guanosine nucleotide exchange factors (GEFs) (Step b). In the active GTP-bound state, RAS proteins can bind a large variety of proximal effectors to stimulate the downstream pathways and biological responses (Step c). The GTPase activating proteins (GAPs) catalyze the hydrolysis of the GTP molecules bound to RAS in order to move the GTPases back to the inactive state at the end of the cell stimulation cycle (Step d). For the sake of simplicity, we have not included in this box additional regulatory layers that can contribute to a further control of the signaling output of RAS proteins (e.g. transcriptional regulation, microRNAs, localization in membrane subregions, posttranslational modifications) [1]. The type of genetic alterations and diseases associated with RAS signaling elements are indicated. For an explanation of the icons used, please check the bottom gray box. In the case of PTPN11, the two stars indicate the two subsets of mutations found in specific RASopathies: GOF mutations that enhance the catalytic activity (found in NS). GOF mutations that, despite reducing or abating the phosphatase activity, enhance the adaptor functions regulated by PTPN11 (found in NSML). iRAS immature RAS; RASGDP, GDP-bound RAS; RASGTP, GTP-bound RAS. Information about mutations in tumors was gathered from the Saint Jude Cloud PeCan (https://pecan.stjude.cloud/home), the cBioPortal (http://www.cbioportal.org) and the IntOGene (https://www.intogen.org/search) databases.

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Figure 1.

Figure 1

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Congenital RASopathies. The main mosaic and germline RASopathies are shown, with information about the genes causing them. Genes undergoing GOF and LOF mutations are shown in red and blue, respectively. RASopathies and groups of genes recently identified are shown in light blue boxes. Previously known RASopathies and RASopathy genes are shown enclosed in light red boxes. Whether some of the KAT6B-related and LZTR1 mutation-related diseases included here develop as a consequence of the direct deregulation of the RAS pathway is unknown as yet. •, Moment in which the mutation causing the disease takes place. The degree of mosaicism elicited by these mutations is depicted as a light red area in the embryo.

Germline and mosaic RASopathies

The first RASopathy identified was the neurofibromatosis type 1 (NF1), which was subsequently shown to be caused by germline loss-of-function (LOF) genetic alterations in the gene encoding the RAS GAP NF1 [2] (Box 1 and Figure 1). Since then, the germline RASopathies identified so far include: First, the Legius syndrome (triggered by LOF alterations in SPRED1, a protein involved in the translocation of NF1 to the plasma membrane) (Box 1 and Figure 1) [2]. Second, the Noonan syndrome (NS), caused by gain-of-function (GOF) mutations in RAS signaling elements that include, among others, catalytically active versions of the PTPN11 phos-phatase (also known as SHP2), the SOS1 GEF, and RAF1 (Box 1 and Figure 1). LOF translocations in KAT6B, a gene encoding a nuclear lysine acetyltransferase involved in the repression of genes encoding RAS pathway signaling elements, have been subsequently identified as well (Box 1 and Figure 1) [4]. Third, the NS with multiple lentigines (NSML), primarily caused by phosphatase-inactive versions of PTPN11 that display enhanced adaptor functions in cells (Box 1 and Figure 1) [2]. Fourth, the NS-like disorder with loose anagen hair, driven by GOF mutations in SHOC2 [2]. This gene encodes a MRAS GTPase binding protein that favors the PP1-mediated dephosphorylation of a RAF negative phosphorylation site (Box 1 and Figure 1) [5]. Fifth, the cardio-facio-cutaneous syndrome, primarily caused by de novo GOF mutations in KRAS, BRAF, MAP2K1 (encoding MEK1), and MAP2K2 (encoding MEK2) (Box 1 and Figure 1). Sixth, the Costello syndrome, mainly caused by de novo HRAS GOF mutations (Box 1 and Figure 1). Seventh, the hereditary gingival neurofibromatosis type 1, which is associated in some cases with SOS1 GOF mutations (Box 1 and Figure 1) [6]. Eighth, the autoimmune lymphoproliferative syndrome, caused by NRAS GOF mutations (Box 1 and Figure 1) [7]. Ninth, the capillary malformation-arteriovenous malformation, triggered by LOF mutations in the gene encoding the RASA1 GAP (Box 1 and Figure 1) [2]. Although phos-phatidylinositol 3 kinase a (PI3Ka) is a well-known downstream RAS element (Box 1), the diseases caused by the deregulation of the PI3Kα−AKT−mTOR axis are usually not included in the list of RASopathies and, therefore, we will not discuss them here (for a review on this topic, see [8]).

New mutant alleles for many of the previously known RASopathy genes still continue to emerge (for recent examples, see [9•,10−12]), indicating that the identification of all possible mutations involved in these diseases is not finished as yet. The roster of genes involved in these pathologies is probably incomplete as well, as inferred from the recent discovery of new loci involved in both NS and NS-like diseases. In the former case, they include additional RAS signaling-related proteins such as the RAS GEF SOS2 [13,14], the RAS-like GTPases RIT1 and RRAS [15,16], the RAS GAP RASA2 [17] and SPRY1, an adaptor protein that acts as a negative regulator of the RAF−ERK axis (Box 1 and Figure 1) [17]. GOF versions of MAP3K8 (also known as Cot or TPL2), a MEK-stimulating serine/threonine kinase, have been also recently found in some NS cases (Box 1 and Figure 1) [17]. In the case of NSML, new genes include those encoding for the rest of members of the SHOC2 complex: the GTPase MRAS and one of the catalytic subunits of the PP1 phosphatase (PPP1CB) (Box 1 and Figure 1) [18•,19•]. Other genes recently identified encode a secreted inhibitor for a wide spectrum of extracellular proteases (A2ML1) [20] and one of the adaptors involved in the function of the CUL3 E3 ubiquitin ligase family (LZTR1) [14] (Figure 1). The mechanistic connection of these two latter proteins with the RAS pathway, if any, remains to be elucidated. However, A2ML1 mutant alleles do elicit NS-like heart and craniofacial defects when introduced in D. rerio embryos indicating that it is a bona fide RASopathy gene [20]. As in the case of previously identified RASopathy genes, germline and/or somatic mutations targeting these newly discovered genes have also been found in tumors (Box 1).

Recent sequencing efforts have revealed that alterations in RAS signaling during embryogenesis probably contribute to other developmental diseases as well, including de novo germline mutations associated with major congenital malformations and severe neurodevelopmental disorders [21•], intellectual disability [22–24], epilepsy [25], autism spectrum disorder [26,27], attention-deficit/hyperactivity problems [28], and multiple schwannomas [29,30] (Figure 1). Many of the ‘classical’ RASopathy genes are probably involved in these developmental processes, as inferred by the high frequency of autism spectrum and attention-deficit/hyperactivity disorders found in RASopathy patients [31•]. De novo mutations of RASopathy genes in postzygotic embryonic periods also contribute to the development of a variety of ‘mosaic’ diseases [32–35,36•,37–41,42••,43–45] (Figure 1). It is likely that the spectrum of RASopathies and the genes involved in them will be further expanded as the genomes of new cohorts of patients become characterized in the near future.

RASopathy mutations: types, origin, and impact during embryogenesis

RASopathies are caused by the mutation of a single allele of the foregoing genes, indicating that most GOF and LOF mutants must exert positive and dominant negative effects in cells, respectively. The mutation of the second allele can occur in subsequent phases of the disease leading, for example, to the generation of tumors in both patients and mouse models [[9•],3]. Concurrent genetic alterations in two RASopathy genes are also observed in a very limited number of cases [46]. The amplification of the wild-type locus of the driver genes is also observed in some germline and mosaic RASopathy patients at low frequency (for recent examples, see [47,48]). In the case of germline RASopathies, the gene mutations originate during gametogenesis (Figure 1). This is probably one of the unavoidable byproducts of the relatively high mutation rates present in germinal cells, a toll we have to pay to facilitate the genetic variation required for our species evolution. In fewer cases, these diseases can also derive from the transmission of a mosaic mutation that includes the germline of one of the parents [49]. The transmission rates of the mutant alleles to the progeny can be further enhanced in some cases (e.g. HRAS, PTPN11) by selfish spermatogonia selection, a process mediated by the enhanced fitness conferred by the RASopathy mutant alleles to spermatogonia [50,51]. It was generally assumed that from this initial pool of mutations only those compatible with embryonic viability could finally trigger the germline RASopathy. Consistent with this idea, the spectra of mutations found in germline RASopathies are usually different from those found both in both cancer and the majority of mosaic RASopathies. Figure 2a and b illustrates this point in the case of HRAS. Furthermore, recent experimental assays have shown that the HRAS and MEK1 mutant proteins exclusively found in tumors show higher activities than those found in both RASopathies and tumors. In turn, these latter mutant proteins are more active than those exclusively found in RASopathies (Figure 2c) [52,53••]. It should be noted, however, that this ‘weaker allele’ model might not explain the different spectrum of mutations found in these diseases in all cases. For example, mutant alleles initially thought to be exclusive of tumors are progressively detected in RASopathies as the numbers of characterized patients increase. The recent characterization of ‘cancer-like’ NRAS mutations in NS patients is a perfect illustration of this tendency [9•]. Thus, it is possible that, at least in some cases, the different frequency of mutations in germline RASopathies could simply reflect the distinct rate in which those mutations occur in the germline when compared to either embryonic or adult cells. This differential mutagenesis process can accurately explain, for example, the frequency of the different HRAS mutant alleles found in Costello syndrome [50].

Figure 2. Example of GOF mutations found in HRAS in RASopathies and cancer.

Figure 2

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(a) HRAS mutations in germline RASopathies (top) and cancer (bottom). The number of times in which a given mutation has been scored is shown in round brackets. These data were collected from the NSEuroNet (https://nseuronet.com/php/statistic.php?choice=variation&genotype=2&) and Saint Jude Cloud PeCan (https://pecan.stjude.cloud/proteinpaint/HRAS) databases, respectively. Additional mutations in cancer have been retrieved from the cBioPortal database (http://www.cbioportal.org/index.do?session_id=5ae209b1498eb8b3d565da41). The three main mutations found in RASopathies are highlighted in dark red in the two disease groups. N, N-terminus; C, C-terminus; G, guanosine nucleotide binding site; SI, switch region I; SII, switch region II. (b) HRAS mutations in indicated mosaic RASopathies (left). The most frequently mutated amino acid positions are shown in larger font. Mutant alleles shared with germline RASopathies are highlighted using red boxes. Data were gathered from original publications. (c) Relative activity of indicated HRAS proteins according to Wey et al. [52]. Mutations with main representation in cancer and germline RASopathies are shown in light red and blue boxes, respectively. Mutations with similar distribution in the two diseases are shaded.

It has been commonly assumed that the effect of the RASopathy mutations is the chronic upregulation of RAS signaling pathways. Multiple studies using animal models and, to a lesser extent patient-derived cells have corroborated this idea [2,3]. However, against this canonical view, recent reports have unexpectedly revealed that the expression of MAP2K1, BRAF and PTPN11 GOF mutant alleles frequently results in either the reduction or total inactivation of ERK signaling in specific areas of the embryo (MAP2K1) and in neuronal subtypes (BRAF, PTPN11) [54••,55••,56••]. These data indicate that the RASopathies can emerge as a consequence of the mosaic activation and repression of ERK1 in different areas of the embryo and adult tissues, an observation that has watershed consequences in terms of the effective implementation of therapies based on dampening the hyperactivity of RAS downstream pathways in RASopathy patients. These data can also explain the unexpected detection of either germline haploinsufficiency or dominant negative mutations in genes that usually exhibit GOF mutations in RASopathies (for recent examples, see [17,57,58•]) (Box 1).

Genetic factors contributing to the variegated phenotype of RASopathies

Each germline RASopathy exhibits unique clinical features that help the diagnosis of patients [2]. Although the biological basis for such specificity remains largely unknown, it is likely that it could be the consequence of the different expression pattern and/or signaling impact of the RASopathy genes involved in each case. For example, the preferential expression of SYNGAP1 in neurons probably explains the linkage of this gene LOF mutations with nervous system disorders (Figure 1). This GAP can also elicit more widespread effects in the nervous system than NF1 given its dual catalytic specificity towards both RAS and RAP GTPases. It is likely that in other cases the different diseases will be the consequence of the presence or absence of compensatory mechanisms by paralogs. For example, the different diseases elicited by LOF mutations in NF1 (NF1) and SPRED1 (Legius syndrome), two proteins that work in the same complex (Figure 1), is probably due to the fact that the loss of SPRED1 is partially compensated by the related SPRED2 in the case of Legius syndrome. Finally, the different disorders can derive from the differential effect of mutant alleles of the same proteins in cell signaling, as is the case of the diverse subsets of PTPN11 mutations found in NS and NSML [59,60•]. Despite the specific clinical features, most RASopathy patients display common phenotypic alterations such as craniofacial malformations, growth delays, neurocognitive impairments, and defects in both the skin and the cardiovascular system. They also have higher risk for specific cancer subtypes, autism spectrum disorder, and attention-deficit-hyperactivity problems [2,31•]. The overlap in the symptomatology of these diseases is epitomized by cases in which patients show clinical features of a specific RASopathy despite bearing mutant alleles most common for another one [17,61–63]. This phenotypic inter-disease similarity is somewhat expected, given that they all eventually derive from alterations in quite similar signaling pathways.

Another common feature of these diseases is that they all show a highly variegated and age-dependent phenotype. Current evidence suggests that this variability stems from both RASopathy gene intrinsic and extrinsic factors. Some of the former factors are connected to the specific protein that becomes deregulated in a given RASopathy, as inferred by the detection of tissue-specific dysfunctions at higher frequency in patients of the same disease that carry different RASopathy genes [[69•]]. This is probably associated with the hierarchical position of the mutant protein within the RAS pathway and/or the intrinsic biochemical function played by the mutant protein. For example, the mutant SOS1 proteins probably elicit wider signaling effects than mutant versions of either RAS or MEK due to its role as a bivalent GEF for RAS and RAC1 GTPases [64]. Signals elicited by the classical RAS proteins are also different from those triggered by the poorly redundant RIT1 and RRAS GTPases [15,16]. Although it is not always the case, some of the variegation in the clinical presentation of the disease is probably due to the specific signaling output of the mutant allele involved. Recent examples of such correlations have been reported for a number of RASopathy mutant alleles [10,65,66]. As indicated above, some of the manifestation of the disease (e.g. cancer) can be also associated with the additional mosaic modification of either the wild-type allele or other tumor suppressor genes during either postzygotic or postnatal periods [3]. Notwithstanding the contribution of these intrinsic factors, a significant part of the phenotypic variability observed in RASopathy patients is caused by ancillary genetic factors as inferred by different levels of disease penetrance in members of the same family (for recent examples, see [20,61,67,68]). In one of these cases, it has been observed for the first time that the symptomatic patients of the family display higher levels of expression of the mutant SOS1 allele than the nonsymptomatic ones [67]. To complicate things further, the penetrance of RASopathies can be even different in twins lacking any obvious change in either SNP polymorphisms or major gene copy number variations [69•]. Although smaller DNA changes cannot be ruled out in this case, these results indicate that the penetrance of the disease can be also influenced by epigenetic and/or environmental factors affecting the development of the phenotype in the embryo. Unfortunately, the identification of the extrinsic factors associated with the phenotypic penetrance of these diseases will be difficult given the limited number of cases available for this type of genetic analyses. Due to the presence of the mutation in a restricted number of embryonic cell lineages, the mosaic RASopathies show more defined, tissue-restricted defects (Figure 1). However, depending on the differentiation stage of the cells where the mutation takes place, the patients can develop in some cases clinical symptoms that resemble those found in patients carrying germline mutations. By analogy with the germline RASopathies, it is likely that the penetrance of these diseases could be also influenced by cooperating genetic and epigenetic factors in trans.

Concluding remarks

Despite the progress made, there are significant challenges laying ahead of us. Some of them pertain to the identification of the molecular basis of the multiple dysfunctions present in patients, a more accurate determination of genotype−phenotype correlations, and the characterization of the genetic factors affecting the penetrance of the disease in patients. These issues will be hard to tackle given the limited number of patients available for this type of studies. Another challenge is to achieve a comprehensive functional cataloguing of the increasing number of genes and mutant alleles that cause these diseases. Many of these issues could be addressed, with the obvious limitations imposed by the use of species that have evolutionarily diverged millions of years ago, using both conventional and more high-throughput animal models. We have already mentioned in this review examples of the utility of this type of assays in this field [53••,54••,55••,56••]. At the end of the road, the key issue is whether we can use this newly generated knowledge to design new therapies to improve the quality of life of patients. This might be difficult given that most defects shown by these patients develop in utero. Another point of uncertainty is related to the recent observation that a significant fraction of the defects present in those diseases might actually derive from reduced rather than elevated signaling from the RAS pathway [54••,55••,56••]. Using a more optimistic perspective, recent animal studies suggest that, at least in the case of specific RASopathy subtypes (e.g. PTPN11-driven NS), some of the neurocognitive deficits do seem to be ameliorated when drugs that reduce RAS signaling are administered in postnatal periods [70]. Preclinical data also suggest that the drug doses that will have to be used to treat these diseases are lower than those used in cancer contexts [53••], a feature that can help avoiding the toxicity associated with most of the available RAS pathway drugs. Given these uncertainties, the most realistic application of these therapies in the near future will be the treatment of patients affected by mosaic RASopathies such as, for example, those showing severe cases of sporadic high flow vascular malformations.

Acknowledgements

The authors wish to apologize to scientists who have not been cited in this work due to space constraints. XRB work is supported by grants from the Castilla-León Government (CSI049U16), Spanish Ministry of Economy and Competitiveness (SAF2015-64556-R), Worldwide Cancer Research (14-1248), Ramón Areces Foundation, and Spanish Society against Cancer (GC16173472GARC). PC work is supported by grants from both the Spanish Ministry of Economy and Competitiveness (SAF-2015 63638R) and the Spanish Society against Cancer (GCB141423113). Funding from Spanish national and regional governments to both XRB and PC is partially contributed by the European Regional Development Fund.

Footnotes

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

•of special interest

• • of outstanding interest

  • 1.Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33. doi: 10.1016/j.cell.2017.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–369. doi: 10.1146/annurev-genom-091212-153523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Jindal GA, Goyal Y, Burdine RD, Rauen KA, Shvartsman SY. RASopathies: unraveling mechanisms with animal models. Dis Model Mech. 2015;8:1167. doi: 10.1242/dmm.022442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, Gordon L, Scott H, Smyth GK, Ahmadian MR, et al. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J Clin Investig. 2011;121:3479–3491. doi: 10.1172/JCI43428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Young LC, Rodriguez-Viciana P. MRAS: a close but understudied member of the RAS family. Cold Spring Harb Perspect Med. 2018 doi: 10.1101/cshperspect.a033621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Hart TC, Zhang Y, Gorry MC, Hart PS, Cooper M, Marazita ML, Marks JM, Cortelli JR, Pallos D. A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet. 2002;70:943–954. doi: 10.1086/339689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 2007;104:8953–8958. doi: 10.1073/pnas.0702975104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C: Semin Med Genet. 2016;172:402–421. doi: 10.1002/ajmg.c.31531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Altmuller F, Lissewski C, Bertola D, Flex E, Stark Z, Spranger S, Baynam G, Buscarilli M, Dyack S, Gillis J, et al. Genotype and phenotype spectrum of NRAS germline variants. Eur J Hum Genet. 2017;25:823–831. doi: 10.1038/ejhg.2017.65. [• Example of the recent identification of cancer-like mutations in RASo-pathy genes as more disease cases are characterized using genomics techniques] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Pannone L, Bocchinfuso G, Flex E, Rossi C, Baldassarre G, Lissewski C, Pantaleoni F, Consoli F, Lepri F, Magliozzi M, et al. Structural, functional, and clinical characterization of a novel PTPN11 mutation cluster underlying Noonan syndrome. Hum Mutat. 2017;38:451–459. doi: 10.1002/humu.23175. [DOI] [PubMed] [Google Scholar]
  • 11.Harms FL, Alawi M, Amor DJ, Tan TY, Cuturilo G, Lissewski C, Brinkmann J, Schanze D, Kutsche K, Zenker M. The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor. Am J Med Genet A. 2018;176:470–476. doi: 10.1002/ajmg.a.38569. [DOI] [PubMed] [Google Scholar]
  • 12.Tafazoli A, Eshraghi P, Pantaleoni F, Vakili R, Moghaddassian M, Ghahraman M, Muto V, Paolacci S, Golyan FF, Abbaszadegan MR. Novel mutations and their genotype−phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci. 2018;63:87–93. doi: 10.1016/j.advms.2017.07.001. [DOI] [PubMed] [Google Scholar]
  • 13.Cordeddu V, Yin JC, Gunnarsson C, Virtanen C, Drunat S, Lepri F, De Luca A, Rossi C, Ciolfi A, Pugh TJ, et al. Activating mutations affecting the Dbl homology domain of SOS2 cause Noonan syndrome. Hum Mutat. 2015;36:1080–1087. doi: 10.1002/humu.22834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015;52:413–421. doi: 10.1136/jmedgenet-2015-103018. [DOI] [PubMed] [Google Scholar]
  • 15.Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93:173–180. doi: 10.1016/j.ajhg.2013.05.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Flex E, Jaiswal M, Pantaleoni F, Martinelli S, Strullu M, Fansa EK, Caye A, De Luca A, Lepri F, Dvorsky R, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014;23:4315–4327. doi: 10.1093/hmg/ddu148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, Peltekova VD, Reid JG, Tworog-Dube E, et al. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci U S A. 2014;111:11473–11478. doi: 10.1073/pnas.1324128111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Gripp KW, Aldinger KA, Bennett JT, Baker L, Tusi J, Powell-Hamilton N, Stabley D, Sol-Church K, Timms AE, Dobyns WB. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. Am J Med Genet A. 2016;170:2237–2247. doi: 10.1002/ajmg.a.37781. [• Work reporting the identification of a new RASopathy gene encoding an additional member of the SHOC2 signaling complex] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Higgins EM, Bos JM, Mason-Suares H, Tester DJ, Ackerman JP, MacRae CA, Sol-Church K, Gripp KW, Urrutia R, Ackerman MJ. Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. JCI Insight. 2017;2:e91225. doi: 10.1172/jci.insight.91225. [• Recent work reporting the identification of a new RASopathy gene encoding the third missing element of the SHOC2 signaling complex: the GTPase MRAS] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Vissers LE, Bonetti M, Paardekooper Overman J, Nillesen WM, Frints SG, de Ligt J, Zampino G, Justino A, Machado JC, Schepens M, et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur J Hum Genet. 2015;23:317–324. doi: 10.1038/ejhg.2014.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–438. doi: 10.1038/nature21062. [• This extensive genome-wide sequencing effort identified mutations in BRAF and SYNGAP1 likely involved in congenital malformations and severe neurodevelopmental disorders] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10:e1004772. doi: 10.1371/journal.pgen.1004772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Cote M, Perreau-Linck E, Carmant L, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360:599–605. doi: 10.1056/NEJMoa0805392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Gannon T, Perveen R, Schlecht H, Ramsden S, Anderson B, Kerr B, Day R, Banka S, Suri M, Berland S, et al. Further delineation of the KAT6B molecular and phenotypic spectrum. Eur J Hum Genet. 2015;23:1165–1170. doi: 10.1038/ejhg.2014.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Mignot C, von Stulpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, Rastetter A, Gachet B, Marie Y, Korenke GC, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53:511–522. doi: 10.1136/jmedgenet-2015-103451. [DOI] [PubMed] [Google Scholar]
  • 26.Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K, Raja A, Coe BP, Stessman HA, He ZX, et al. Excess of rare, inherited truncating mutations in autism. Nat Genet. 2015;47:582–588. doi: 10.1038/ng.3303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, Kushima I, Okada T, Morikawa M, Uno Y, et al. Integrative analyses of de novo mutations provide deeper biological insights into autism spectrum disorder. Cell Rep. 2018;22:734–747. doi: 10.1016/j.celrep.2017.12.074. [DOI] [PubMed] [Google Scholar]
  • 28.Xu Y, Chen XT, Luo M, Tang Y, Zhang G, Wu D, Yang B, Ruan DY, Wang HL. Multiple epigenetic factors predict the attention deficit/hyperactivity disorder among the Chinese Han children. J Psychiatr Res. 2015;64:40–50. doi: 10.1016/j.jpsychires.2015.03.006. [DOI] [PubMed] [Google Scholar]
  • 29.Piotrowski A, Xie J, Liu YF, Poplawski AB, Gomes AR, Madanecki P, Fu C, Crowley MR, Crossman DK, Armstrong L, et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2014;46:182–187. doi: 10.1038/ng.2855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Paganini I, Chang VY, Capone GL, Vitte J, Benelli M, Barbetti L, Sestini R, Trevisson E, Hulsebos TJ, Giovannini M, et al. Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur J Hum Genet. 2015;23:963–968. doi: 10.1038/ejhg.2014.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Garg S, Brooks A, Burns A, Burkitt-Wright E, Kerr B, Huson S, Emsley R, Green J. Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway. Dev Med Child Neurol. 2017;59:544–549. doi: 10.1111/dmcn.13394. [• Extensive epidemiological study convincingly extending the clinical phenotype of several RASopathies to autism spectrum and attention-deficit] [DOI] [PubMed] [Google Scholar]
  • 32.Colman SD, Rasmussen SA, Ho VT, Abernathy CR, Wallace MR. Somatic mosaicism in a patient with neurofibromatosis type 1. Am J Hum Genet. 1996;58:484–490. [PMC free article] [PubMed] [Google Scholar]
  • 33.Gripp KW, Stabley DL, Nicholson L, Hoffman JD, Sol-Church K. Somatic mosaicism for an HRAS mutation causes Costello syndrome. Am J Med Genet A. 2006;140:2163–2169. doi: 10.1002/ajmg.a.31456. [DOI] [PubMed] [Google Scholar]
  • 34.Peacock JD, Dykema KJ, Toriello HV, Mooney MR, Scholten DJ, Winn ME, Borgman A, Duesbery NS, Hiemenga JA, Liu C, et al. Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am J Med Genet A. 2015;167:1429–1435. doi: 10.1002/ajmg.a.37048. [DOI] [PubMed] [Google Scholar]
  • 35.Hafner C, Toll A, Gantner S, Mauerer A, Lurkin I, Acquadro F, Fernandez-Casado A, Zwarthoff EC, Dietmaier W, Baselga E, et al. Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J Med Genet. 2012;49:249–253. doi: 10.1136/jmedgenet-2011-100637. [DOI] [PubMed] [Google Scholar]
  • 36.Lim YH, Ovejero D, Derrick KM, Collins MT, Choate KA Yale Center for Mendelian G. Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J Am Acad Dermatol. 2016;75:420–427. doi: 10.1016/j.jaad.2015.11.012. [• A recent example of a new mosaic RASopathy] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Groesser L, Herschberger E, Ruetten A, Ruivenkamp C, Lopriore E, Zutt M, Langmann T, Singer S, Klingseisen L, Schneider-Brachert W, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012;44:783–787. doi: 10.1038/ng.2316. [DOI] [PubMed] [Google Scholar]
  • 38.Charbel C, Fontaine RH, Malouf GG, Picard A, Kadlub N, ElMurr N, How-Kit A, Su X, Coulomb-L’Hermine A, Tost J, et al. NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J Investig Dermatol. 2014;134:1067–1074. doi: 10.1038/jid.2013.429. [DOI] [PubMed] [Google Scholar]
  • 39.Salgado CM, Basu D, Nikiforova M, Hamilton RL, Gehris R, Jakacki R, Panigrahy A, Yatsenko S, Reyes-Mugica M. Amplification of mutated NRAS leading to congenital melanoma in neurocutaneous melanocytosis. Melanoma Res. 2015;25:453–460. doi: 10.1097/CMR.0000000000000188. [DOI] [PubMed] [Google Scholar]
  • 40.Ramesh R, Shaw N, Miles EK, Richard B, Colmenero I, Moss C. Mosaic NRAS Q61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets. Clin Exp Dermatol. 2017;42:75–79. doi: 10.1111/ced.12969. [DOI] [PubMed] [Google Scholar]
  • 41.Etchevers HC, Rose C, Kahle B, Vorbringer H, Fina F, Heux P, Berger I, Schwarz B, Zaffran S, Macagno N, et al. Giant congenital melanocytic nevus with vascular malformation and epidermal cysts associated with a somatic activating mutation in BRAF. Pigment Cell Melanoma Res. 2018;31:437–441. doi: 10.1111/pcmr.12685. [DOI] [PubMed] [Google Scholar]
  • 42.Al-Olabi L, Polubothu S, Dowsett K, Andrews KA, Stadnik P, Joseph AP, Knox R, Pittman A, Clark G, Baird W, et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Investig. 2018;128:1496–1508. doi: 10.1172/JCI98589. [•• An example of a report on a new mosaic RASopathy, which includes functional assays using the D. rerio model. This work also demonstrates that the vascular defects induced by BRAF mutants can be eliminated using the BRAF kinase inhibitor vemurasenib] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, Hammer F, Amor DJ, Irvine AD, Baselga E, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34:1632–1641. doi: 10.1002/humu.22431. [DOI] [PubMed] [Google Scholar]
  • 44.Farschtschi S, Mautner VF, Pham M, Nguyen R, Kehrer-Sawatzki H, Hutter S, Friedrich RE, Schulz A, Morrison H, Jones DT, et al. Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. Ann Neurol. 2016;80:625–628. doi: 10.1002/ana.24753. [DOI] [PubMed] [Google Scholar]
  • 45.Krupp DR, Barnard RA, Duffourd Y, Evans SA, Mulqueen RM, Bernier R, Riviere JB, Fombonne E, O’Roak BJ. Exonic mosaic mutations contribute risk for autism spectrum disorder. Am J Hum Genet. 2017;101:369–390. doi: 10.1016/j.ajhg.2017.07.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Ekvall S, Hagenas L, Allanson J, Anneren G, Bondeson ML. Cooccurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 2011;155A:1217–1224. doi: 10.1002/ajmg.a.33987. [DOI] [PubMed] [Google Scholar]
  • 47.Salem B, Hofherr S, Turner J, Doros L, Smpokou P. Childhood rhabdomyosarcoma in association with a RASopathy clinical phenotype and mosaic germline SOS1 duplication. J Pediatr Hematol Oncol. 2016;38:e278–e282. doi: 10.1097/MPH.0000000000000566. [DOI] [PubMed] [Google Scholar]
  • 48.Gilbert-Dussardier B, Briand-Suleau A, Laurendeau I, Bilan F, Cave H, Verloes A, Vidaud M, Vidaud D, Pasmant E. Copy number variants and rasopathies: germline KRAS duplication in a patient with syndrome including pigmentation abnormalities. Orphanet J Rare Dis. 2016;11:101. doi: 10.1186/s13023-016-0479-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Sol-Church K, Stabley DL, Demmer LA, Agbulos A, Lin AE, Smoot L, Nicholson L, Gripp KW. Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism. Am J Med Genet A. 2009;149A:315–321. doi: 10.1002/ajmg.a.32639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Giannoulatou E, McVean G, Taylor IB, McGowan SJ, Maher GJ, Iqbal Z, Pfeifer SP, Turner I, Burkitt Wright EM, Shorto J, et al. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. Proc Natl Acad Sci U S A. 2013;110:20152–20157. doi: 10.1073/pnas.1311381110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Yoon SR, Choi SK, Eboreime J, Gelb BD, Calabrese P, Arnheim N. Age-dependent germline mosaicism of the most common Noonan syndrome mutation shows the signature of germline selection. Am J Hum Genet. 2013;92:917–926. doi: 10.1016/j.ajhg.2013.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Wey M, Lee J, Jeong SS, Kim J, Heo J. Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome. Biochemistry. 2013;52:8465–8479. doi: 10.1021/bi400679q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Jindal GA, Goyal Y, Yamaya K, Futran AS, Kountouridis I, Balgobin CA, Schupbach T, Burdine RD, Shvartsman SY. In vivo severity ranking of Ras pathway mutations associated with developmental disorders. Proc Natl Acad Sci U S A. 2017;114:510–515. doi: 10.1073/pnas.1615651114. [•• Using the D. rerio and D. melanogaster animal models, these authors comprehensively characterize a large number of RASopathy-associated and cancer-associated MEK1 mutations. On the basis of these experiments, they classify the bioactivity of the MEK1 mutant proteins in the following rank: cancer-specific MEK1 mutants > MEK1 mutants shared by cancer and RASopathy patients > RASopathy-specific MEK1 mutants. They also find that the drug doses required to inhibit the RASopathy mutant proteins are probably lower than those needed to abate the activity of the cancer-linked mutant ones] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Goyal Y, Jindal GA, Pelliccia JL, Yamaya K, Yeung E, Futran AS, Burdine RD, Schupbach T, Shvartsman SY. Divergent effects of intrinsically active MEK variants on developmental Ras signaling. Nat Genet. 2017;49:465–469. doi: 10.1038/ng.3780. [•• Using genetic techniques in D. rerio and D. melanogaster models, the authors show that active MEK1 mutants can unexpectedly trigger either the stimulation or the silencing of the ERK pathway depending upon the region of the embryo where they are expressed. This work, together with those reported in Refs. [55••,56••], indicates that part of the RASopathy phenotype can be a consequence of the repression rather than the stimulation of RAS downstream signaling] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Lim CS, Kang X, Mirabella V, Zhang H, Bu Q, Araki Y, Hoang ET, Wang S, Shen Y, Choi S, et al. BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method. Genes Dev. 2017;31:537–552. doi: 10.1101/gad.294413.116. [•• Using a quite impressive lentiviral-based genetic tour-de-force with la large number of mutant versions of BRAF frequently found in RASopathies and/or tumors, the authors show that the GOF and LOF mutations in this kinase unexpectedly trigger the same defects in specific neuronal subtypes from rats, mice, and humans. In addition, they identify the implication of BRAF in the synaptic NMDA sensitive glutamate receptor−Ca2+/calmodulin-dependent protein kinase II−SYNGAP1−RAS−ERK pathway. Dysfunction in that pathway are probably connected to the cognitive impairment phenotype found in cardio-facio-cutaneous syndrome patients] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Altmuller F, Pothula S, Annamneedi A, Nakhaei-Rad S, Montenegro-Venegas C, Pina-Fernandez E, Marini C, Santos M, Schanze D, Montag D, et al. Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy. PLoS Genet. 2017;13:e1006684. doi: 10.1371/journal.pgen.1006684. [•• Using a tissue-specific mouse model, this group demonstrates that the expression of a NS-specific PTNPN11 mutant allele in mice leads to the reduction of the ERK-dependent responses in forebrain neurons. By contrast, it promotes the activation of other signaling pathways in those cells. This dowmodulation seems to be associated with the transcriptional upregulation of inhibitory elements of the RAS−ERK pathway] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Nowaczyk MJ, Thompson BA, Zeesman S, Moog U, Sanchez-Lara PA, Magoulas PL, Falk RE, Hoover-Fong JE, Batista DA, Amudhavalli SM, et al. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin Genet. 2014;85:138–146. doi: 10.1111/cge.12116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Linhares ND, Freire MC, Cardenas RG, Pena HB, Lachlan K, Dallapiccola B, Bacino C, Delobel B, James P, Thuresson AC, et al. 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency. Genet Mol Biol. 2016;39:349–357. doi: 10.1590/1678-4685-GMB-2016-0049. [• A recent example of a haploinsufficiency in a driver RASopathy gene] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Stewart RA, Sanda T, Widlund HR, Zhu S, Swanson KD, Hurley AD, Bentires-Alj M, Fisher DE, Kontaridis MI, Look AT, et al. Phosphatase-dependent and-independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. Dev Cell. 2010;18:750–762. doi: 10.1016/j.devcel.2010.03.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Zheng H, Yu WM, Waclaw RR, Kontaridis MI, Neel BG, Qu CK. Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner. Sci Signal. 2018:11. doi: 10.1126/scisignal.aao1591. [• A good example of the dissociation of the phenotypic effects of NS and NSML-associated PTPN11 mutations in the brain] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Santoro C, Giugliano T, Melone MAB, Cirillo M, Schettino C, Bernardo P, Cirillo G, Perrotta S, Piluso G. Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype. Clin Genet. 2018;93:138–143. doi: 10.1111/cge.13047. [DOI] [PubMed] [Google Scholar]
  • 62.Ekvall S, Sjors K, Jonzon A, Vihinen M, Anneren G, Bondeson ML. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2014;164A:579–587. doi: 10.1002/ajmg.a.36313. [DOI] [PubMed] [Google Scholar]
  • 63.Nishi E, Mizuno S, Nanjo Y, Niihori T, Fukushima Y, Matsubara Y, Aoki Y, Kosho T. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. Am J Med Genet A. 2015;167A:407–411. doi: 10.1002/ajmg.a.36842. [DOI] [PubMed] [Google Scholar]
  • 64.Chen PC, Wakimoto H, Conner D, Araki T, Yuan T, Roberts A, Seidman C, Bronson R, Neel B, Seidman JG, et al. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. J Clin Investig. 2010;120:4353–4365. doi: 10.1172/JCI43910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Bertola D, Buscarilli M, Stabley DL, Baker L, Doyle D, Bartholomew DW, Sol-Church K, Gripp KW. Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp. Am J Med Genet A. 2017;173:1309–1318. doi: 10.1002/ajmg.a.38178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Hartung AM, Swensen J, Uriz IE, Lapin M, Kristjansdottir K, Petersen US, Bang JM, Guerra B, Andersen HS, Dobrowolski SF, et al. The splicing efficiency of activating HRAS mutations can determine Costello syndrome phenotype and frequency in cancer. PLoS Genet. 2016;12:e1006039. doi: 10.1371/journal.pgen.1006039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Moncini S, Bonati MT, Morella I, Ferrari L, Brambilla R, Riva P. Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family. Eur J Hum Genet. 2015;23:1531–1537. doi: 10.1038/ejhg.2015.20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, et al. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018 doi: 10.1038/gim.2017.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Sites ER, Smolarek TA, Martin LJ, Viskochil DH, Stevenson DA, Ullrich NJ, Messiaen LM, Schorry EK. Analysis of copy number variants in 11 pairs of monozygotic twins with neurofibromatosis type 1. Am J Med Genet A. 2017;173:647–653. doi: 10.1002/ajmg.a.38058. [• This work does not find any recurrent SNP or gene copy number variation that can explain the variegated phenotype of NF1 in a series of NF1 mutation-bearing twins. It also includes in the introduction the description of previous work reporting the different penetrance of this disease in twins] [DOI] [PubMed] [Google Scholar]
  • 70.Lee YS, Ehninger D, Zhou M, Oh JY, Kang M, Kwak C, Ryu HH, Butz D, Araki T, Cai Y, et al. Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome. Nat Neurosci. 2014;17:1736–1743. doi: 10.1038/nn.3863. [DOI] [PMC free article] [PubMed] [Google Scholar]

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