{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:19:27Z","timestamp":1769001567231,"version":"3.49.0"},"reference-count":32,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T00:00:00Z","timestamp":1701561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"NCN research projects","doi-asserted-by":"publisher","award":["2016\/21\/N\/HS6\/02891"],"award-info":[{"award-number":["2016\/21\/N\/HS6\/02891"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Noonan syndrome (NS) is one of the most common genetic conditions inherited mostly in an autosomal dominant manner with vast heterogeneity in clinical and genetic features. Patients with NS might have speech disturbances, memory and attention deficits, limitations in daily functioning, and decreased overall intelligence. Here, 34 patients with Noonan syndrome and 23 healthy controls were enrolled in a study involving gray and white matter volume evaluation using voxel-based morphometry (VBM), white matter connectivity measurements using diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Fractional anisotropy (FA) and mean diffusivity (MD) probability distributions were calculated. Cognitive abilities were assessed using the Stanford Binet Intelligence Scales. Reductions in white matter connectivity were detected using DTI in NS patients. The rs-fMRI revealed hyper-connectivity in NS patients between the sensorimotor network and language network and between the sensorimotor network and salience network in comparison to healthy controls. NS patients exhibited decreased verbal and nonverbal IQ compared to healthy controls. The assessment of the microstructural alterations of white matter as well as the resting-state functional connectivity (rsFC) analysis in patients with NS may shed light on the mechanisms responsible for cognitive and neurofunctional impairments.<\/jats:p>","DOI":"10.3390\/genes14122173","type":"journal-article","created":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T04:59:16Z","timestamp":1701579556000},"page":"2173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma\u2013Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-7989","authenticated-orcid":false,"given":"Natalia","family":"Braun-Walicka","sequence":"first","affiliation":[{"name":"The Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Pluta","sequence":"additional","affiliation":[{"name":"The Bioimaging Research Center, World Hearing Center, Institute of Physiology and Pathology of Hearing, Kajetany, 05-830 Nadarzyn, Poland"},{"name":"The Faculty of Psychology, University of Warsaw, 00-183 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6473-8392","authenticated-orcid":false,"given":"Tomasz","family":"Wolak","sequence":"additional","affiliation":[{"name":"The Bioimaging Research Center, World Hearing Center, Institute of Physiology and Pathology of Hearing, Kajetany, 05-830 Nadarzyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edyta","family":"Maj","sequence":"additional","affiliation":[{"name":"The Bioimaging Research Center, World Hearing Center, Institute of Physiology and Pathology of Hearing, Kajetany, 05-830 Nadarzyn, Poland"},{"name":"2nd Department of Clinical Radiology, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7213-6554","authenticated-orcid":false,"given":"Agnieszka","family":"Maryniak","sequence":"additional","affiliation":[{"name":"The Faculty of Psychology, University of Warsaw, 00-183 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Gos","sequence":"additional","affiliation":[{"name":"The Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Abramowicz","sequence":"additional","affiliation":[{"name":"The Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5920-1312","authenticated-orcid":false,"given":"Aleksandra","family":"Landowska","sequence":"additional","affiliation":[{"name":"The Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Obersztyn","sequence":"additional","affiliation":[{"name":"The Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerzy","family":"Bal","sequence":"additional","affiliation":[{"name":"The Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/gim.2017.249","article-title":"Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants","volume":"20","author":"Johnston","year":"2018","journal-title":"Genet. Med."},{"key":"ref_2","first-page":"285","article-title":"The RASopathies as an example of RAS\/MAPK pathway disturbances\u2014Clinical presentation and molecular pathogenesis of selected syndromes","volume":"18","author":"Bezniakow","year":"2014","journal-title":"Dev. Period. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61.e1","DOI":"10.1016\/j.anpedi.2020.04.008","article-title":"Noonan syndrome: Genetic and clinical update and treatment options","volume":"93","author":"Carcavilla","year":"2020","journal-title":"An. Pediatr. Engl. Ed."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5734\/JGM.2019.16.1.1","article-title":"Noonan syndrome and RASopathies: Clinical features, diagnosis and management","volume":"16","author":"Lee","year":"2019","journal-title":"J. Genet. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","article-title":"The RASopathies: Developmental syndromes of Ras\/MAPK pathway dysregulation","volume":"19","author":"Tidyman","year":"2009","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/353170a0","article-title":"Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases","volume":"353","author":"Cohen","year":"1991","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1038\/sj.onc.1210392","article-title":"Differential regulation and properties of MAPKs","volume":"26","author":"Raman","year":"2007","journal-title":"Oncogene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0022-3476(99)70089-2","article-title":"Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression","volume":"135","author":"Thoonen","year":"1999","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1002\/ajmg.a.36374","article-title":"Behavioral profile in RASopathies","volume":"164A","author":"Alfieri","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/dmcn.12621","article-title":"Attention skills and executive functioning in children with Noonan syndrome and their unaffected siblings","volume":"57","author":"Pierpont","year":"2015","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/j.1601-183X.2008.00469.x","article-title":"Genotype differences in cognitive functioning in Noonan syndrome","volume":"8","author":"Pierpont","year":"2009","journal-title":"Genes. Brain Behav."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/ajmg.a.32488","article-title":"Cognitive profile of disorders associated with dysregulation of the RAS\/MAPK signaling cascade","volume":"149A","author":"Cesarini","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_13","first-page":"505","article-title":"Understanding Voxel-Based Morphometry","volume":"69","author":"Nemoto","year":"2017","journal-title":"Brain Nerve."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00234-010-0717-2","article-title":"The efficacy of a voxel-based morphometry on the analysis of imaging in schizophrenia, temporal lobe epilepsy, and Alzheimer\u2019s disease\/mild cognitive impairment: A review","volume":"52","author":"Kakeda","year":"2010","journal-title":"Neuroradiology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.mri.2008.09.004","article-title":"Effects of interpolation methods in spatial normalization of diffusion tensor imaging data on group comparison of fractional anisotropy","volume":"27","author":"Chao","year":"2009","journal-title":"Magn. Reson. Imaging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.neuroimage.2011.10.063","article-title":"The future of fMRI and genetics research","volume":"62","year":"2012","journal-title":"Neuroimage"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1744-9081-10-33","article-title":"Reduced resting-state brain activity in the default mode network in children with (central) auditory processing disorders","volume":"10","author":"Pluta","year":"2014","journal-title":"Behav. Brain Funct. BBF"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1007\/s11682-021-00460-5","article-title":"Resting-state abnormalities in functional connectivity of the default mode network in autism spectrum disorder: A meta-analysis","volume":"15","author":"Wang","year":"2021","journal-title":"Brain Imaging Behav."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1750-1172-2-4","article-title":"Noonan syndrome","volume":"2","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_20","unstructured":"Roid, G.H., Sajewicz-Radtke, U., Radtke, B.M., and Lipowska, M. (2017). Stanford-Binet Intelligence Scales, Laboratory of Psychological and Pedagogical Tests. [5th ed.]. (In Polish)."},{"key":"ref_21","unstructured":"R Core Team (2021). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v042.i08","article-title":"MatchIt: Nonparametric Preprocessing for Parametric Causal Inference","volume":"42","author":"Ho","year":"2011","journal-title":"J. Stat. Softw."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.neuroimage.2012.01.068","article-title":"Connectivity differences in brain networks","volume":"60","author":"Zalesky","year":"2012","journal-title":"Neuroimage"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S208","DOI":"10.1016\/j.neuroimage.2004.07.051","article-title":"Advances in functional and structural MR image analysis and implementation as FSL","volume":"23","author":"Smith","year":"2004","journal-title":"Neuroimage"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroimage.2010.06.010","article-title":"Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature","volume":"53","author":"Destrieux","year":"2010","journal-title":"Neuroimage"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1093\/cercor\/bhaa299","article-title":"PTPN11 Mutations in the Ras-MAPK Signaling Pathway Affect Human White Matter Microstructure","volume":"31","author":"Fattah","year":"2021","journal-title":"Cereb. Cortex."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1093\/cercor\/bhy158","article-title":"PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention","volume":"29","author":"Johnson","year":"2019","journal-title":"Cereb. Cortex."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wingberm\u00fchle, E., Roelofs, R.L., Oomens, W., Kramer, J., Draaisma, J.M.T., Leenders, E., Kleefstra, T., Kessels, R.P.C., and Egger, J.I.M. (2022). Cognitive Phenotype and Psychopathology in Noonan Syndrome Spectrum Disorders through Various Ras\/MAPK Pathway Associated Gene Variants. J. Clin. Med., 11.","DOI":"10.3390\/jcm11164735"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00381-012-2000-9","article-title":"Association between Noonan syndrome and Chiari I malformation: A case-based update","volume":"29","author":"Keh","year":"2013","journal-title":"Childs Nerv. Syst."},{"key":"ref_30","first-page":"408","article-title":"Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS\/MAPK pathway","volume":"60","author":"Ejarque","year":"2015","journal-title":"Rev. Neurol."},{"key":"ref_31","unstructured":"Toga, A.W. (2015). Brain Mapping: An Encyclopedic Reference, Elsevier."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1111\/j.1601-183X.2012.00821.x","article-title":"Cognitive functioning of adults with Noonan syndrome: A case-control study","volume":"11","author":"Roelofs","year":"2012","journal-title":"Genes. Brain Behav."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/12\/2173\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:36:49Z","timestamp":1760132209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/12\/2173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,3]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["genes14122173"],"URL":"https:\/\/doi.org\/10.3390\/genes14122173","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,3]]}}}