{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:48:25Z","timestamp":1760244505939,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008750","name":"Shanghai \u201cRising Stars of Medical Talents\u201d Youth Development Program and Clinical Research Plan of SHDC","doi-asserted-by":"publisher","award":["SHDC2020CR6028"],"award-info":[{"award-number":["SHDC2020CR6028"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype\u2013phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence and severity of neurological phenotypes. Exome sequencing data were used to identify genetic variants in 13 NF1 patients and 457 healthy controls, and this information was used to identify candidate modifier genes underlying neurological phenotypes based on an optimal sequence kernel association test. Thirty-six genes were identified as significant modifying factors in patients with neurological phenotypes and all are highly expressed in the nervous system. A review of the literature confirmed that 19 genes including CUL7, DPH1, and BCO1 are clearly associated with the alteration of neurological functioning and development. Our study revealed the enrichment of rare variants of 19 genes closely related to neurological development and functioning in NF1 patients with neurological phenotypes, indicating possible modifier genes and variants affecting neurodevelopment. Further studies on rare genetic variants of candidate modifier genes may help explain the clinical heterogeneity of NF1.<\/jats:p>","DOI":"10.3390\/genes13122218","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T04:01:33Z","timestamp":1669608093000},"page":"2218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of Rare Genetic Variants to Identify Candidate Modifier Genes Underlying Neurological Manifestations in Neurofibromatosis 1 Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Jie","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6504-7633","authenticated-orcid":false,"given":"Niu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoqiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3391-5250","authenticated-orcid":false,"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4147-5291","authenticated-orcid":false,"given":"Ruen","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/ajmg.a.33139","article-title":"Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service","volume":"152","author":"Evans","year":"2010","journal-title":"Am. 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