{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:51:46Z","timestamp":1790985106154,"version":"4.1.0"},"reference-count":18,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"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>Objective: Ventriculomegaly is the main prenatal imaging feature for diagnosing fetal central nervous system anomalies in humans. Many ventriculomegalies can be related to genetic causes, regardless of their imaging presentations. Among these, MPDZ variants have been reported to cause severe ventriculomegaly inherited in an autosomal recessive manner (OMIM#615219). Several hypotheses have been put forward linking MPDZ variants to ventriculomegaly, but the precise underlying mechanisms, in particular whether its origin is obstructive or non-obstructive, are yet to be elucidated. Methods: To address this question, we retrospectively analyzed pre- and postnatal neuro-imaging and neuropathological data for cases of ventriculomegaly in which MPDZ variants were found through exome or genome sequencing. We performed anti-MPDZ immunostaining on fetal brain samples. Results: We analyzed six cases (four fetuses and two children) of ventriculomegaly of variable severities with MPDZ variants. The precise analysis of brain MRI data, corroborated by fetopathological examinations, demonstrated an obstructive pattern of ventriculomegaly upstream from partial fusion of the thalami, also called diencephalosynapsis, with partial atresia of the third ventricle, which could extend to Sylvius\u2019s aqueduct. Conclusions: The morphological analysis using targeted brain magnetic resonance imaging (MRI) and neuropathological data allowed us to unravel the underlying mechanisms of congenital ventriculomegaly related to MDPZ variants.<\/jats:p>","DOI":"10.3390\/genes16060707","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T14:03:11Z","timestamp":1750082591000},"page":"707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MPDZ Pathogenic Variants Cause Obstructive Ventriculomegaly Related to Diencephalosynapsis and Third Ventricle Atresia"],"prefix":"10.3390","volume":"16","author":[{"given":"Sara","family":"Cabet","sequence":"first","affiliation":[{"name":"Pediatric and Fetal Imaging Department, Femme-M\u00e8re-Enfant Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, 69500 Lyon, France"},{"name":"Institut NeuroMyoG\u00e8ne, CNRS UMR5292, INSERM U1028, Claude Bernard Lyon 1 University, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Ghersi-Egea","sequence":"additional","affiliation":[{"name":"Fluid Team, Lyon Neurosciences Research Center, CNRS UMR5292, INSERM U1028, Claude Bernard Lyon 1 University, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6476-6345","authenticated-orcid":false,"given":"Suonavy","family":"Khung-Savatovsky","sequence":"additional","affiliation":[{"name":"Functional Unit of Fetal Pathology, Department of Genetics, Robert-Debr\u00e9 Hospital, AP-HP, 75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-9538","authenticated-orcid":false,"given":"Fabien","family":"Guimiot","sequence":"additional","affiliation":[{"name":"Functional Unit of Fetal Pathology, Department of Genetics, Robert-Debr\u00e9 Hospital, AP-HP, 75019 Paris, France"},{"name":"INSERM U1141, Paris-Cite University, 75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5496-4604","authenticated-orcid":false,"given":"Audrey","family":"Putoux","sequence":"additional","affiliation":[{"name":"Department of Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Sabatier","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Femme-M\u00e8re-Enfant Hospital, Hospices Civils de Lyon, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Felix Guyon Hospital, 97490 Saint-Denis, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Raymond","sequence":"additional","affiliation":[{"name":"Genetic Department, Eurofins Biomnis, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2914-1961","authenticated-orcid":false,"given":"J\u00e9r\u00e9mie","family":"Mortreux","sequence":"additional","affiliation":[{"name":"Genetic Department, Eurofins Biomnis, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Laurichesse Delmas","sequence":"additional","affiliation":[{"name":"Multidisciplinary Prenatal Diagnosis Center, University Hospital Center of Clermont Ferrand, 63000 Clermont Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice Eric","family":"Cuillier","sequence":"additional","affiliation":[{"name":"Fetal Imaging Department, Felix Guyon Hospital, 97490 Saint-Denis, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Ho","sequence":"additional","affiliation":[{"name":"Imagerie Capricorne, Clinique Sainte-Clotilde, 97490 Saint-Denis, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-9492","authenticated-orcid":false,"given":"Gaetan","family":"Lesca","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoG\u00e8ne, CNRS UMR5292, INSERM U1028, Claude Bernard Lyon 1 University, 69500 Lyon, France"},{"name":"Department of Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Alessandri","sequence":"additional","affiliation":[{"name":"Genetic Department, Felix Guyon Hospital, La R\u00e9union University, 97490 Saint-Denis, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Guibaud","sequence":"additional","affiliation":[{"name":"Pediatric and Fetal Imaging Department, Femme-M\u00e8re-Enfant Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, 69500 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/uog.6456","article-title":"Fetal cerebral ventricular measurement and ventriculomegaly: Time for procedure standardization","volume":"34","author":"Guibaud","year":"2009","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/uog.12427","article-title":"Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation","volume":"42","author":"Cagneaux","year":"2013","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/uog.14687","article-title":"Etiological diagnostic tools to elucidate \u201cisolated\u201d ventriculomegaly","volume":"46","author":"Guibaud","year":"2015","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_4","unstructured":"UniProt Consortium (2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523\u2013D531."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Al-Jezawi, N.K., Al-Shamsi, A.M., Suleiman, J., Ben-Salem, S., John, A., Vijayan, R., Ali, B.R., and Al-Gazali, L. (2018). Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0540-x"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1136\/jmedgenet-2012-101294","article-title":"Mutation in MPDZ causes severe congenital hydrocephalus","volume":"50","author":"Tulbah","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/ana.24964","article-title":"The genetic landscape of familial congenital hydrocephalus","volume":"81","author":"Shaheen","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40478-017-0438-4","article-title":"Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene","volume":"5","author":"Marguet","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"890","DOI":"10.15252\/emmm.201606430","article-title":"Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice","volume":"9","author":"Feldner","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12987-022-00323-1","article-title":"Cerebrospinal fluid production by the choroid plexus: A century of barrier research revisited","volume":"19","author":"MacAulay","year":"2022","journal-title":"Fluids Barriers CNS"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e9540","DOI":"10.15252\/emmm.201809540","article-title":"Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus","volume":"11","author":"Yang","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40478-023-01519-8","article-title":"Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla","volume":"11","author":"Tessier","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/pd.4323","article-title":"Dilatation of the supra-pineal recess on prenatal imaging: Early clue for obstructive ventriculomegaly downstream of the third ventricle","volume":"34","author":"Azzi","year":"2014","journal-title":"Prenat. Diagn."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1002\/acn3.51448","article-title":"L1CAM variants cause two distinct imaging phenotypes on fetal MRI","volume":"8","author":"Accogli","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_15","first-page":"600","article-title":"Ultrasonographic and pathological correlation in a fetal intracranial cyst: A case of \u201cdiencephalo-synapsis\u201d","volume":"31","author":"Saada","year":"2002","journal-title":"J. Gynecol. Obstet. Biol. Reprod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/pd.6106","article-title":"Prenatal imaging features related to RAC3 pathogenic variant and differential diagnoses","volume":"42","author":"Cabet","year":"2022","journal-title":"Prenat. Diagn."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1080\/13816810.2022.2161580","article-title":"Retinal manifestations in autosomal recessive MPDZ maculopathy: Report of two cases and literature review","volume":"44","author":"Iyengar","year":"2023","journal-title":"Ophthalmic Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, S., Zhang, F., Wang, J., Yang, S., Ren, Y., Rui, X., Xia, X., and Sheng, X. (2022). Novel Compound Heterozygous Variations in MPDZ Gene Caused Isolated Bilateral Macular Coloboma in a Chinese Family. Cells, 11.","DOI":"10.3390\/cells11223602"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/6\/707\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:51:50Z","timestamp":1760032310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/6\/707"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,13]]},"references-count":18,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["genes16060707"],"URL":"https:\/\/doi.org\/10.3390\/genes16060707","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,13]]}}}