{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:17:22Z","timestamp":1788405442752,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pathogenic variants in\n                    <jats:italic>LZTR1<\/jats:italic>\n                    are an established cause of Noonan syndrome (NS) and uniquely exhibit both autosomal dominant (AD) and autosomal recessive (AR) inheritance. However, the phenotypic spectrum and genotype\u2013phenotype correlations remain incompletely defined. We conducted a multi\u2010center retrospective chart review of patients diagnosed with\n                    <jats:italic>LZTR1<\/jats:italic>\n                    \u2010NS evaluated at three tertiary care centers. Clinical, molecular, and imaging data were systematically collected. A comprehensive literature review (2015\u20132025) identified 100 additional individuals meeting inclusion criteria. Comparative analyses were performed to evaluate phenotypic patterns by inheritance. Among 21 previously unreported patients aged 6\u2009months to 49\u2009years, 15 had AD NS and 6 had AR NS. Clinical features were largely consistent with prior reports, including high prevalence of craniofacial dysmorphism, neurodevelopmental and multisystem involvement. Cardiac manifestations were frequent, with pulmonary valve stenosis as the most common lesion. Hypertrophic cardiomyopathy appeared more prominent among AR NS. Notably, lymphatic abnormalities were observed at a higher frequency than previously reported. Compared to the literature, our cohort highlights novel findings, including the co\u2010occurrence of AD\n                    <jats:italic>LZTR1<\/jats:italic>\n                    \u2010NS with 22q11.2 deletion and two patients with AR NS with features suggestive of schwannomatosis. These findings expand the clinical spectrum of\n                    <jats:italic>LZTR1<\/jats:italic>\n                    \u2010NS and have important implications for diagnosis, surveillance, and genetic counseling.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70297","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:09:16Z","timestamp":1788404956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Evaluation of Molecular Genetics and Clinical Manifestations in Patients With\n                    <scp>\n                      <i>LZTR1<\/i>\n                    <\/scp>\n                    \u2010Associated Noonan Syndrome: A Retrospective Chart Review and Review of Literature"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6806-0072","authenticated-orcid":false,"given":"Hager","family":"Jaouadi","sequence":"first","affiliation":[{"name":"Division of Cardiology Cincinnati Children's Hospital  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eakir","family":"Hicazi","sequence":"additional","affiliation":[{"name":"Division of Cardiology Cincinnati Children's Hospital  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7488-2662","authenticated-orcid":false,"given":"Carolyn R.","family":"Raski","sequence":"additional","affiliation":[{"name":"Edwards Family Division of Genetics &amp; Rare Diseases Ann &amp; Robert H. Lurie Children's Hospital of Chicago  Chicago Illinois USA"},{"name":"Department of Pediatrics Feinberg School of Medicine, Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Aschbacher\u2010Smith","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada","family":"Hijazi","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Cardiology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Division of Genetics, Department of Pediatrics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos E.","family":"Prada","sequence":"additional","affiliation":[{"name":"Edwards Family Division of Genetics &amp; Rare Diseases Ann &amp; Robert H. Lurie Children's Hospital of Chicago  Chicago Illinois USA"},{"name":"Department of Pediatrics Feinberg School of Medicine, Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Nicole","family":"Weaver","sequence":"additional","affiliation":[{"name":"Division of Cardiology Cincinnati Children's Hospital  Cincinnati Ohio USA"},{"name":"Division of Human Genetics Cincinnati Children's Hospital  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/s41418-019-0395-5","article-title":"LZTR1 Facilitates Polyubiquitination and Degradation of RAS\u2010GTPases","volume":"27","author":"Abe T.","year":"2020","journal-title":"Cell Death and Differentiation"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/chd.12721","article-title":"Prevalence of Noonan Spectrum Disorders in a Pediatric Population With Valvar Pulmonary Stenosis","volume":"14","author":"Anderson K.","year":"2019","journal-title":"Congenital Heart Disease"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/jhg.2015.114","article-title":"Recent Advances in RASopathies","volume":"61","author":"Aoki Y.","year":"2016","journal-title":"Journal of Human Genetics"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"e63905","DOI":"10.1002\/ajmg.a.63905","article-title":"New Insights Into the Spectrum of RASopathies\u2009: Clinical and Genetic Data in a Cohort of 121 Spanish Patients","volume":"197","author":"Barbero A. I. S.","year":"2025","journal-title":"American Journal of Medical Genetics. Part A"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"114448","DOI":"10.1016\/j.celrep.2024.114448","article-title":"Mutation\u2010Induced LZTR1 Polymerization Provokes Cardiac Pathology in Recessive Noonan Syndrome","volume":"43","author":"Busley A. V.","year":"2024","journal-title":"Cell Reports"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ajmg.a.61445","article-title":"Providing More Evidence on LZTR1 Variants in Noonan Syndrome Patients","volume":"182","author":"Chinton J.","year":"2020","journal-title":"American Journal of Medical Genetics. Part A"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/humu.24376","article-title":"Comparison of the Frequency of Loss\u2010Of\u2010Function LZTR1 Variants Between Schwannomatosis Patients and the General Population","volume":"43","author":"Deng F.","year":"2022","journal-title":"Human Mutation"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1126\/science.adv7088","article-title":"Structural Basis for LZTR1 Recognition of RAS GTPases for Degradation","volume":"389","author":"Dharmaiah S.","year":"2025","journal-title":"Science"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"e63518","DOI":"10.1002\/ajmg.a.63518","article-title":"Biallelic LZTR1 Variants in a 49\u2010Year\u2010Old Woman With Hypertrophic Cardiomyopathy: A Clue for Considering LZTR1 in Adults","volume":"194","author":"Di Stolfo G.","year":"2024","journal-title":"American Journal of Medical Genetics"},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s12920-022-01304-x","article-title":"LZTR1 Molecular Genetic Overlap With Clinical Implications for Noonan Syndrome and Schwannomatosis","volume":"15","author":"Farncombe K. M.","year":"2022","journal-title":"BMC Medical Genomics"},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1038\/s41431-020-0658-0","article-title":"Digenic Inheritance of Subclinical Variants in Noonan Syndrome Patients: An Alternative Pathogenic Model?","volume":"28","author":"Ferrari L.","year":"2020","journal-title":"European Journal of Human Genetics"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ppedcard.2015.01.002","article-title":"Cardiomyopathies in Noonan Syndrome and the Other RASopathies","volume":"39","author":"Gelb B. D.","year":"2015","journal-title":"Progress in Pediatric Cardiology"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41525-025-00505-4","article-title":"Assessing the Diagnostic Impact of Blood Transcriptome Profiling in a Pediatric Cohort Previously Assessed by Genome Sequencing","volume":"10","author":"Hou H.","year":"2025","journal-title":"NPJ Genomic Medicine"},{"key":"e_1_2_11_15_1","first-page":"e002690","article-title":"LZTR1 \u2010Related Hypertrophic Cardiomyopathy Without Typical Noonan Syndrome Features","volume":"13","author":"Jenkins J.","year":"2020","journal-title":"Circulation: Genomic and Precision Medicine"},{"key":"e_1_2_11_16_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 J. J.","year":"2018","journal-title":"Genetics in Medicine"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"1312357","DOI":"10.3389\/fendo.2024.1312357","article-title":"Undiagnosed RASopathies in Infertile Men","volume":"15","author":"Juchnewitsch A.\u2010G.","year":"2024","journal-title":"Frontiers in Endocrinology"},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"102123","DOI":"10.1016\/j.omtn.2024.102123","article-title":"Preclinical Evaluation of CRISPR\u2010Based Therapies for Noonan Syndrome Caused by Deep\u2010Intronic LZTR1 Variants","volume":"35","author":"Knauer C.","year":"2024","journal-title":"Molecular Therapy \u2010 Nucleic Acids"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.21037\/tp-24-113","article-title":"Noonan Syndrome and Noonan\u2010Like Syndrome With Loose Anagen Hair: Rare Phenotypes May Emerge During Follow\u2010Up","volume":"13","author":"Liu Z.","year":"2024","journal-title":"Translational Pediatrics"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"101241","DOI":"10.1016\/j.gim.2024.101241","article-title":"Heterozygosity for Loss\u2010Of\u2010Function Variants in LZTR1 Is Associated With Isolated Multiple caf\u00e9\u2010Au\u2010Lait Macules","volume":"26","author":"Mastromoro G.","year":"2024","journal-title":"Genetics in Medicine"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1093\/hmg\/ddy412","article-title":"Dominant Noonan Syndrome\u2010Causing LZTR1 Mutations Specifically Affect the Kelch Domain Substrate\u2010Recognition Surface and Enhance RAS\u2010MAPK Signaling","volume":"28","author":"Motta M.","year":"2019","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"e1107","DOI":"10.1002\/mgg3.1107","article-title":"Noonan Syndrome\u2010Associated Biallelic LZTR1 Mutations Cause Cardiac Hypertrophy and Vascular Malformations in Zebrafish","volume":"8","author":"Nakagama Y.","year":"2020","journal-title":"Molecular Genetics & Genomic Medicine"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1177\/000992289403300907","article-title":"Noonan Syndrome. An Update and Review for the Primary Pediatrician","volume":"33","author":"Noonan J. A.","year":"1994","journal-title":"Clinical Pediatrics (Phila)"},{"key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/ejhg.2014.220","article-title":"Expanding the Mutational Spectrum of LZTR1 in Schwannomatosis","volume":"23","author":"Paganini I.","year":"2015","journal-title":"European Journal of Human Genetics"},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/cge.13533","article-title":"Delineation of Dominant and Recessive Forms of LZTR1 \u2010Associated Noonan Syndrome","volume":"95","author":"Pagnamenta A. T.","year":"2019","journal-title":"Clinical Genetics"},{"key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/ng.2855","article-title":"Germline Loss\u2010Of\u2010Function Mutations in LZTR1 Predispose to an Inherited Disorder of Multiple Schwannomas","volume":"46","author":"Piotrowski A.","year":"2014","journal-title":"Nature Genetics"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/ajmg.a.35760","article-title":"Update From the 2011 International Schwannomatosis Workshop: From Genetics to Diagnostic Criteria","volume":"161","author":"Plotkin S. R.","year":"2013","journal-title":"American Journal of Medical Genetics. Part A"},{"key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.3390\/ijms26083515","article-title":"Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review","volume":"26","author":"Reynolds G.","year":"2025","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology., Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards S.","year":"2015","journal-title":"Genetics in Medicine: Official Journal of the American College of Medical Genetics"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts A. E.","year":"2013","journal-title":"Lancet (London, England)"},{"key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1212\/WNL.0000000000001129","article-title":"Mutations in LZTR1 Add to the Complex Heterogeneity of Schwannomatosis","volume":"84","author":"Smith M. J.","year":"2015","journal-title":"Neurology"},{"key":"e_1_2_11_32_1","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1126\/science.aap7607","article-title":"Mutations in LZTR1 Drive Human Disease by Dysregulating RAS Ubiquitination","volume":"362","author":"Steklov M.","year":"2018","journal-title":"Science"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ajmg.c.32012","article-title":"The Molecular Genetics of RASopathies\u2009: An Update on Novel Disease Genes and New Disorders","volume":"190","author":"Tartaglia M.","year":"2022","journal-title":"American Journal of Medical Genetics. Part C, Seminars in Medical Genetics"},{"key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"916","DOI":"10.3390\/genes15070916","article-title":"Phenotypic Expansion of Autosomal Dominant LZTR1\u2010Related Disorders With Special Emphasis on Adult\u2010Onset Features","volume":"15","author":"Uliana V.","year":"2024","journal-title":"Genes"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00439-018-1951-7","article-title":"Delineation of LZTR1 Mutation\u2010Positive Patients With Noonan Syndrome and Identification of LZTR1 Binding to RAF1\u2013PPP1CB Complexes","volume":"138","author":"Umeki I.","year":"2019","journal-title":"Human Genetics"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","first-page":"4450","DOI":"10.1002\/ehf2.14944","article-title":"Biventricular Outflow Tract Obstruction due to Hypertrophy Related to Compound Heterozygous Variants in LZTR1","volume":"11","author":"Wang S.","year":"2024","journal-title":"ESC Heart Failure"},{"key":"e_1_2_11_37_1","article-title":"Prevalence of Genetic Diagnoses in a Cohort With Valvar Pulmonary Stenosis","volume":"15","author":"Weaver K. N.","year":"2022","journal-title":"Circulation: Genomic and Precision Medicine"},{"key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/jmedgenet-2015-103018","article-title":"Rare Variants in SOS2 and LZTR1 Are Associated With Noonan Syndrome","volume":"52","author":"Yamamoto G. L.","year":"2015","journal-title":"Journal of Medical Genetics"},{"key":"e_1_2_11_39_1","doi-asserted-by":"crossref","first-page":"147723","DOI":"10.1016\/j.ijbiomac.2025.147723","article-title":"Lztr1 Deficiency Contributes to the Pathogenesis of Dilated Cardiomyopathy via RAP1\/PI3K\/AKT\u2010Mediated Myocardial Injury","volume":"329","author":"Yang L.","year":"2025","journal-title":"International Journal of Biological Macromolecules"},{"key":"e_1_2_11_40_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41525-025-00512-5","article-title":"Sequencing Validates Deep Learning Models for EHR\u2010Based Detection of Noonan Syndrome in Pediatric Patients","volume":"10","author":"Yang Z.","year":"2025","journal-title":"NPJ Genomic Medicine"},{"key":"e_1_2_11_41_1","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1002\/pd.6462","article-title":"Prenatal Diagnosis of Autosomal Recessive Noonan Syndrome Associated With Biallelic LZTR1 Variants Presented With Thick Nuchal Translucency and Cardiac Abnormalities","volume":"43","author":"Yu Q.\u2010X.","year":"2023","journal-title":"Prenatal Diagnosis"},{"key":"e_1_2_11_42_1","doi-asserted-by":"crossref","first-page":"114691","DOI":"10.1016\/j.ejogrb.2025.114691","article-title":"Clinical and Molecular Analysis of Seventy\u2010One Fetal Cases With RASopathies","volume":"314","author":"Yu Q.\u2010X.","year":"2025","journal-title":"European Journal of Obstetrics, Gynecology, and Reproductive Biology"},{"key":"e_1_2_11_43_1","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3892\/ol.2021.12825","article-title":"LZTR1: A Promising Adaptor of the CUL3 Family","volume":"22","author":"Zhang H.","year":"2021","journal-title":"Oncology Letters"},{"key":"e_1_2_11_44_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12902-020-00666-6","article-title":"A Chinese Family With Noonan Syndrome Caused by a Heterozygous Variant in LZTR1: A Case Report and Literature Review","volume":"21","author":"Zhao X.","year":"2021","journal-title":"BMC Endocrine Disorders"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70297","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70297","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70297","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:09:27Z","timestamp":1788404967000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":43,"alternative-id":["10.1002\/ajmg.a.70297"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70297","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"assertion":[{"value":"2026-04-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ajmg.a.70297"}}