{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T18:22:19Z","timestamp":1777141339522,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in KIDINS220 cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them. Methods: We performed whole exome sequencing (WES) and a literature and mutation databases review. Results: We report a young adult with SP, severe ID, strabismus, and macrocephaly exhibiting brain malformations at follow-up, partially overlapping with those described in TUBB3 tubulinopathy. WES analysis of the proband and parents identified the heterozygous de novo variant (NM_020738.4: c. 4144G &gt; T) p. Glu 1382* in KIDINS220 that was predicted to be causative of SINO. Conclusions: The progression of myelination and the development of brain structures turned out to be crucial for identifying, at follow-up, the whole KIDINS220-related brain malformations. The truncated proteins associated with SINO lack a portion fundamental for the interaction of kidins220 with tubulins and microtubule-associated proteins. The complexity of the brain malformations displayed by our patient, and possibly by other reported SINO patients, could result from an impaired dynamic modulation of the microtubule cytoskeleton during embryogenesis. Brain malformations must be considered as part of the SINO spectrum phenotype.<\/jats:p>","DOI":"10.3390\/genes15091190","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T04:35:24Z","timestamp":1725942924000},"page":"1190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Novel KIDINS220 Pathogenic Variant Associated with the Syndromic Spastic Paraplegia SINO: An Expansion of the Brain Malformation Spectrum and a Literature Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8024-0482","authenticated-orcid":false,"given":"Maria Teresa","family":"Bonati","sequence":"first","affiliation":[{"name":"Institute for Maternal and Child Health \u201cBurlo Garofolo\u201d, 34137 Trieste, TS, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Baldoli","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, San Raffaele Scientific Institute, 20132 Milan, MI, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacopo","family":"Taurino","sequence":"additional","affiliation":[{"name":"Cardiovascular-Genetic Center, IRCCS Policlinico San Donato, 20097 San Donato Milanese, MI, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, 24127 Bergamo, BG, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1367-7227","authenticated-orcid":false,"given":"Lidia","family":"Larizza","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Cusano Milanino, MI, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8464-6906","authenticated-orcid":false,"given":"Palma","family":"Finelli","sequence":"additional","affiliation":[{"name":"SC Patologia Clinica, SS Laboratorio Genetica Medica, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, MI, Italy"},{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, MI, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, 24127 Bergamo, BG, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1038\/sj.emboj.7600253","article-title":"A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein","volume":"23","author":"Yano","year":"2004","journal-title":"EMBO J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1091\/mbc.e06-05-0453","article-title":"Kidins220\/ARMS is transported by a kinesin-1-based mechanism likely to be involved in neuronal differentiation","volume":"18","author":"Bracale","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1074\/jbc.M109.024703","article-title":"Kidins220\/ARMS modulates the activity of microtubule-regulating proteins and controls neuronal polarity and development","volume":"285","author":"Higuero","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Scholz-Starke, J., Cesca, F., Schiavo, G., Benfenati, F., and Baldelli, P. (2012). Kidins220\/ARMS is a novel modulator of short-term synaptic plasticity in hippocampal GABAergic neurons. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035785"},{"key":"ref_5","first-page":"1845","article-title":"Kidins220\/ARMS as a functional mediator of multiple receptor signalling pathways","volume":"125","author":"Neubrand","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1093\/hmg\/ddw082","article-title":"Heterozygous KIDINS220\/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity","volume":"25","author":"Josifova","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.1111\/ene.13600","article-title":"Heterozygous KIDINS220 mutation leads to spastic paraplegia and obesity in an Asian girl","volume":"25","author":"Yang","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhang, K., Sun, W., Liu, Y., Lv, Y., Hou, D., Lin, Y., Xu, W., Zhao, J., Gai, Z., and Zhao, S. (2021). SINO Syndrome Causative KIDINS220\/ARMS Gene Regulates Adipocyte Differentiation. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.619475"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s40291-019-00426-w","article-title":"Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia","volume":"23","author":"Zhao","year":"2019","journal-title":"Mol. Diagn. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1093\/hmg\/ddx263","article-title":"Homozygous KIDINS220 loss-of-function variants in fetuses with cerebral ventriculomegaly and limb contractures","volume":"26","author":"Mero","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1093\/hmg\/ddaa245","article-title":"TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly","volume":"29","author":"Jacquemin","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1002\/ajmg.a.61858","article-title":"Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant","volume":"182","author":"Issa","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1159\/000522486","article-title":"Pre- and Postnatal Characterization of Autosomal Recessive KIDINS220-Associated Ventriculomegaly","volume":"13","author":"Brady","year":"2022","journal-title":"Mol. Syndromol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1002\/ajmg.a.40635","article-title":"Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy","volume":"176","author":"Pezzani","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","unstructured":"(2024, August 18). CinVar, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/."},{"key":"ref_16","unstructured":"(2024, August 18). HGMD\u00ae Professional. Available online: https:\/\/apps.ingenuity.com\/ingsso\/login."},{"key":"ref_17","unstructured":"(2024, August 05). PubMed, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Deciphering Developmental Disorders Study (2017). Prevalence and architecture of de novo mutations in developmental disorders. Nature, 542, 433\u2013438.","DOI":"10.1038\/nature21062"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/j.ajhg.2019.11.003","article-title":"Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders","volume":"105","author":"Turner","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.cell.2009.12.011","article-title":"Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance","volume":"140","author":"Tischfield","year":"2010","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.gde.2011.01.003","article-title":"Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations","volume":"21","author":"Tischfield","year":"2011","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4462","DOI":"10.1093\/hmg\/ddq377","article-title":"Mutations in the neuronal \u00df-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects","volume":"19","author":"Poirier","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/2051-5960-2-69","article-title":"Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly","volume":"2","author":"Poirier","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/RMR.0000000000000188","article-title":"Tubulinopathies","volume":"27","author":"Freddi","year":"2018","journal-title":"Top. Magn. Reson. Imaging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1007\/s00330-018-5610-0","article-title":"The spectrum of brainstem malformations associated to mutations of the tubulin genes family: MRI and DTI analysis","volume":"29","author":"Arrigoni","year":"2019","journal-title":"Eur. Radiol."},{"key":"ref_26","unstructured":"(2024, July 05). GeneReviews\u00ae\u2013NCBI Bookshel, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1116\/."},{"key":"ref_27","unstructured":"(2024, June 10). Orphanet. Available online: https:\/\/www.orpha.net\/."},{"key":"ref_28","unstructured":"(2024, August 01). OMIM, Available online: https:\/\/www.ncbi.nlm.nih.gov\/omim\/."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Schmieg, N., Thomas, C., Yabe, A., Lynch, D.S., Iglesias, T., Chakravarty, P., and Schiavo, G. (2015). Novel Kidins220\/ARMS Splice Isoforms: Potential Specific Regulators of Neuronal and Cardiovascular Development. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129944"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Albini, M., Almacellas-Barbanoj, A., Krawczun-Rygmaczewska, A., Ciano, L., Benfenati, F., Michetti, C., and Cesca, F. (2024). Alterations in KIDINS220\/ARMS Expression Impact Sensory Processing and Social Behavior in Adult Mice. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042334"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1111\/ene.13693","article-title":"Kidins220\/ARMS transgenic lines could be instrumental in the understanding of the molecular mechanisms leading to spastic paraplegia and obesity","volume":"25","author":"Cesca","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41420-022-00854-4","article-title":"Kidins220\/ARMS modulates brain morphology and anxiety-like traits in adult mice","volume":"8","author":"Albini","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00401-013-1146-1","article-title":"Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: Evidence for closely related clinical entities of unknown molecular bases","volume":"126","author":"Delezoide","year":"2013","journal-title":"Acta Neuropathol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/9\/1190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:52:47Z","timestamp":1760111567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/9\/1190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,10]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["genes15091190"],"URL":"https:\/\/doi.org\/10.3390\/genes15091190","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,10]]}}}