{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:56:00Z","timestamp":1789516560634,"version":"build-2803163510"},"reference-count":65,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","doi-asserted-by":"publisher","award":["PI23\/01370"],"award-info":[{"award-number":["PI23\/01370"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","doi-asserted-by":"publisher","award":["B32_20R"],"award-info":[{"award-number":["B32_20R"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Spanish Ministry of Health-ISCIII Fondo de Investigaci\u00f3n Sanitaria (FIS)","doi-asserted-by":"publisher","award":["JIUZ2023-SAL-06"],"award-info":[{"award-number":["JIUZ2023-SAL-06"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["PI23\/01370"],"award-info":[{"award-number":["PI23\/01370"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["B32_20R"],"award-info":[{"award-number":["B32_20R"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n-FEDER: European Social Fund","award":["JIUZ2023-SAL-06"],"award-info":[{"award-number":["JIUZ2023-SAL-06"]}]},{"DOI":"10.13039\/501100007041","name":"University of Zaragoza","doi-asserted-by":"publisher","award":["PI23\/01370"],"award-info":[{"award-number":["PI23\/01370"]}],"id":[{"id":"10.13039\/501100007041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007041","name":"University of Zaragoza","doi-asserted-by":"publisher","award":["B32_20R"],"award-info":[{"award-number":["B32_20R"]}],"id":[{"id":"10.13039\/501100007041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007041","name":"University of Zaragoza","doi-asserted-by":"publisher","award":["JIUZ2023-SAL-06"],"award-info":[{"award-number":["JIUZ2023-SAL-06"]}],"id":[{"id":"10.13039\/501100007041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite significant advances in gene discovery, the molecular basis of many rare genetic disorders remains poorly understood. The concept of disease modules, clusters of functionally related genes whose disruption leads to overlapping phenotypes, offers a valuable framework for interpreting these conditions. However, identifying such relationships remains particularly challenging in ultra-rare syndromes due to the limited number of documented cases. We hypothesized that AI-based facial phenotyping could aid in identifying shared molecular mechanisms by detecting phenotypic convergence among clinically related syndromes. To test this, we used Schuurs\u2013Hoeijmakers syndrome (SHMS; OMIM #615009), caused by a recurrent de novo variant in PACS1, as a model to explore potential phenotypic and functional associations with PACS2-related disorder (DEE66; OMIM #618067) and WDR37-related disorder (NOCGUS; OMIM #618652). Facial photographs of individuals with SHMS were analyzed using the DeepGestalt and GestaltMatcher algorithms. In addition to consistently recognizing SHMS as a distinct clinical entity, the algorithms frequently matched DEE66 and NOCGUS, suggesting a shared facial gestalt. Binary comparisons further confirmed overlapping craniofacial features among the three disorders. These findings were supported by literature review, indicating clinical overlapping and potential functional associations. Overall, our results confirm the presence of consistent facial similarities among PACS1-, PACS2-, and WDR37-related syndromes and highlight the utility of AI-driven facial phenotyping as a complementary tool for uncovering clinically relevant relationships in ultra-rare genetic disorders.<\/jats:p>","DOI":"10.3390\/ijms26167964","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T16:22:33Z","timestamp":1755534153000},"page":"7964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0882-5352","authenticated-orcid":false,"given":"Julia","family":"del Rinc\u00f3n","sequence":"first","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6858-1575","authenticated-orcid":false,"given":"Marta","family":"Gil-Salvador","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Lucia-Campos","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Acero","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Trujillano","sequence":"additional","affiliation":[{"name":"Clinical and Molecular Genetics Area, Vall d\u2019Hebron Hospital, Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-2157","authenticated-orcid":false,"given":"Mar\u00eda","family":"Arnedo","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6051-4254","authenticated-orcid":false,"given":"Pilar","family":"Pamplona","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"},{"name":"Unit of Neurophysiology, University Hospital Lozano Blesa, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0023-8137","authenticated-orcid":false,"given":"Ariadna","family":"Ayerza-Casas","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"},{"name":"Unit of Paediatric Cardiology, Service of Paediatrics, University Hospital Miguel Servet, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0170-7326","authenticated-orcid":false,"given":"Beatriz","family":"Puisac","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-2209","authenticated-orcid":false,"given":"Feliciano J.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics, Service of Paediatrics, Department of Paediatrics, University Hospital Lozano Blesa, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3203-6254","authenticated-orcid":false,"given":"Juan","family":"Pi\u00e9","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4703-6620","authenticated-orcid":false,"given":"Ana","family":"Latorre-Pellicer","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV2 and IIS-Aragon-GIIS062, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41431-019-0508-0","article-title":"Estimating cumulative point prevalence of rare diseases: Analysis of the Orphanet database","volume":"28","author":"Wakap","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_2","unstructured":"Online Mendelian Inheritance in Man, OMIM\u00ae (2025, July 22). McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). Available online: https:\/\/omim.org."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/d41573-022-00019-z","article-title":"Research on rare diseases: Ten years of progress and challenges at IRDiRC","volume":"21","author":"Monaco","year":"2022","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ajhg.2017.04.003","article-title":"International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases","volume":"100","author":"Boycott","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.ajhg.2019.07.011","article-title":"Mendelian Gene Discovery: Fast and Furious with No End in Sight","volume":"105","author":"Bamshad","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature21062","article-title":"Prevalence and architecture of de novo mutations in developmental disorders","volume":"542","author":"McRae","year":"2017","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1038\/s41591-019-0581-5","article-title":"A framework for the investigation of rare genetic disorders in neuropsychiatry","volume":"25","author":"Sanders","year":"2019","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101123","DOI":"10.1016\/j.isci.2020.101123","article-title":"Rare Genetic Diseases: Nature\u2019s Experiments on Human Development","volume":"23","author":"Lee","year":"2020","journal-title":"iScience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.tins.2020.05.004","article-title":"Neurodevelopmental Disorders: From Genetics to Functional Pathways","volume":"43","author":"Parenti","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6306","DOI":"10.1038\/s41467-021-26674-1","article-title":"Network analysis reveals rare disease signatures across multiple levels of biological organization","volume":"12","author":"Buphamalai","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e635","DOI":"10.1016\/S2589-7500(21)00137-0","article-title":"Development and evaluation of a machine learning-based point-of-care screening tool for genetic syndromes in children: A multinational retrospective study","volume":"3","author":"Porras","year":"2021","journal-title":"Lancet Digit. Health"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hennocq, Q., Willems, M., Amiel, J., Arpin, S., Attie-Bitach, T., Bongibault, T., Bouygues, T., Cormier-Daire, V., Corre, P., and Dieterich, K. (2024). Next generation phenotyping for diagnosis and phenotype-genotype correlations in Kabuki syndrome. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-52691-3"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1007\/s00431-023-04937-x","article-title":"Computer-aided facial analysis as a tool to identify patients with Silver-Russell syndrome and Prader-Willi syndrome","volume":"182","author":"Ciancia","year":"2023","journal-title":"Eur. J. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41591-018-0279-0","article-title":"Identifying facial phenotypes of genetic disorders using deep learning","volume":"25","author":"Gurovich","year":"2019","journal-title":"Nat. Med."},{"key":"ref_16","first-page":"e19263","article-title":"Efficiency of Computer-Aided Facial Phenotyping (DeepGestalt) in Individuals with and Without a Genetic Syndrome: Diagnostic Accuracy Study","volume":"22","author":"Pantel","year":"2020","journal-title":"J. Med. Int. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Latorre-Pellicer, A., Ascaso, \u00c1., Trujillano, L., Gil-Salvador, M., Arnedo, M., Lucia-Campos, C., Anto\u00f1anzas-P\u00e9rez, R., Marcos-Alcalde, I., Parenti, I., and Bueno-Lozano, G. (2020). Evaluating face2gene as a tool to identify cornelia de lange syndrome by facial phenotypes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031042"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41588-021-01010-x","article-title":"GestaltMatcher facilitates rare disease matching using facial phenotype descriptors","volume":"54","author":"Hsieh","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.ajhg.2012.10.013","article-title":"Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome","volume":"91","author":"Oh","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1093\/emboj\/20.9.2191","article-title":"PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic","volume":"20","author":"Crump","year":"2001","journal-title":"EMBO J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1038\/s41388-020-1167-x","article-title":"The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability","volume":"39","author":"Mani","year":"2020","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6547","DOI":"10.1038\/s41467-023-42176-8","article-title":"Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy","volume":"14","author":"Thomas","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Arnedo, M., Ascaso, \u00c1., Latorre-Pellicer, A., Lucia-Campos, C., Gil-Salvador, M., Ayerza-Casas, A., Pablo, M.J., G\u00f3mez-Puertas, P., Ramos, F.J., and Bueno-Lozano, G. (2022). Molecular Basis of the Schuurs-Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179649"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/ajmg.a.62020","article-title":"Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis","volume":"185","author":"Sakaguchi","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1007\/s00439-021-02384-y","article-title":"WDR37 syndrome: Identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins","volume":"140","author":"Sorokina","year":"2021","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"iyae118","DOI":"10.1093\/genetics\/iyae118","article-title":"PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1\/PACS2 syndromes","volume":"228","author":"Byrd","year":"2024","journal-title":"Genetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/ajmg.a.37476","article-title":"Clinical delineation of the PACS1-related syndrome--Report on 19 patients","volume":"170","author":"Landsverk","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/cge.12544","article-title":"Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability","volume":"88","author":"Gadzicki","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tenorio-Casta\u00f1o, J., Morte, B., Nevado, J., Martinez-Glez, V., Santos-Simarro, F., Garc\u00eda-Mi\u00f1a\u00far, S., Palomares-Bralo, M., Pacio-M\u00edguez, M., G\u00f3mez, B., and Arias, P. (2021). Schuurs-Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review. Genes, 12.","DOI":"10.3390\/genes12050738"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/ajmg.a.9","article-title":"Schuurs-Hoeijmakers syndrome in two patients from Japan","volume":"179","author":"Hoshino","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1159\/000507562","article-title":"Renpenning Syndrome in a Turkish Patient: de novo Variant c.607C>T in PACS1 and Hypogammaglobulinemia Phenotype","volume":"11","author":"Eyerci","year":"2020","journal-title":"Mol. Syndromol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e04897","DOI":"10.1002\/ccr3.4897","article-title":"Schuurs-Hoeijmakers syndrome in a patient from Iraq-Kirkuk","volume":"9","author":"Abdulqader","year":"2021","journal-title":"Clin. Case Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.ajhg.2018.03.005","article-title":"A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis","volume":"102","author":"Olson","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1684\/epd.2022.1417","article-title":"First reported case of an inherited PACS2 pathogenic variant with variable expression","volume":"24","author":"Cesaroni","year":"2022","journal-title":"Epileptic Disord."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.seizure.2020.05.001","article-title":"A further contribution to the delineation of epileptic phenotype in PACS2-related syndrome","volume":"79","author":"Terrone","year":"2020","journal-title":"Seizure"},{"key":"ref_36","first-page":"716","article-title":"New case with the recurrent c.635G>A pathogenic variant in the PACS2 gene: Expanding the phenotype","volume":"36","year":"2021","journal-title":"Neurologia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/cge.13516","article-title":"Expanding the clinical spectrum associated with PACS2 mutations","volume":"95","author":"Dentici","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_38","first-page":"43","article-title":"Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature","volume":"25","author":"Thevenon","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1002\/ajmg.a.61816","article-title":"Protein elongation variant of PUF60: Milder phenotypic end of the Verheij syndrome","volume":"182","author":"Yamada","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/ejhg.2017.27","article-title":"PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features","volume":"25","author":"Low","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1002\/ajmg.a.62950","article-title":"The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome","volume":"188","author":"Fennell","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/cge.13795","article-title":"Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants","volume":"98","author":"Hay","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ajhg.2019.06.015","article-title":"De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome","volume":"105","author":"Reis","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ajhg.2019.06.014","article-title":"De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia","volume":"105","author":"Kanca","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Nie, K., Huang, J., Liu, L., Lv, H., Chen, D., and Fan, W. (2022). Identification of a De Novo Heterozygous Missense ACTB Variant in Baraitser-Winter Cerebrofrontofacial Syndrome. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.828120"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1002\/humu.23970","article-title":"Further delineation of putative ACTB loss-of-function variants: A 4-patient series","volume":"41","author":"Baumann","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"103877","DOI":"10.1016\/j.ejmg.2020.103877","article-title":"Previously undescribed phenotypic findings and novel ACTG1 gene pathogenic variants in Baraitser-Winter cerebrofrontofacial syndrome","volume":"63","author":"Villarroel","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1002\/ajmg.a.61637","article-title":"Baraitser-Winter cerebrofrontofacial syndrome: Report of two adult siblings","volume":"182","author":"Hampshire","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1002\/ajmg.a.37771","article-title":"Update on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome","volume":"170","author":"Kuechler","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/ejhg.2014.95","article-title":"Baraitser-Winter cerebrofrontofacial syndrome: Delineation of the spectrum in 42 cases","volume":"23","author":"Verloes","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D1333","DOI":"10.1093\/nar\/gkad1005","article-title":"The Human Phenotype Ontology in 2024: Phenotypes around the world","volume":"52","author":"Gargano","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_52","first-page":"115","article-title":"The future role of facial image analysis in ACMG classification guidelines","volume":"35","author":"Krawitz","year":"2023","journal-title":"Med. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Pagano, S., Lopergolo, D., De Falco, A., Meossi, C., Satolli, S., Pasquariello, R., Trovato, R., Tessa, A., Casalini, C., and Pfanner, L. (2025). Expanding the Clinical Spectrum Associated with the Recurrent Arg203Trp Variant in PACS1: An Italian Cohort Study. Genes, 16.","DOI":"10.3390\/genes16020227"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Latorre-Pellicer, A., Trujillano, L., del Rinc\u00f3n, J., Pe\u00f1a-Marco, M., Gil-Salvador, M., Lucia-Campos, C., Arnedo, M., Puisac, B., Ramos, F.J., and Ayerza-Casas, A. (2023). Heart Disease Characterization and Myocardial Strain Analysis in Patients with PACS1 Neurodevelopmental Disorder. J. Clin. Med., 12.","DOI":"10.3390\/jcm12124052"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e42904","DOI":"10.2196\/42904","article-title":"Validation of 3 Computer-Aided Facial Phenotyping Tools (DeepGestalt, GestaltMatcher, and D-Score): Comparative Diagnostic Accuracy Study","volume":"26","author":"Reiter","year":"2024","journal-title":"J. Med. Internet Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1038\/s41591-023-02448-8","article-title":"Large language models in medicine","volume":"29","author":"Thirunavukarasu","year":"2023","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s13023-025-03656-w","article-title":"Comparative analysis of large language models on rare disease identification","volume":"20","author":"Ao","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_58","unstructured":"(2025, July 23). BrainSpan: Atlas of the Developing Human Brain; Allen Institute for Brain Science. Available online: https:\/\/www.brainspan.org."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s41576-023-00594-w","article-title":"Shaping faces: Genetic and epigenetic control of craniofacial morphogenesis","volume":"24","author":"Selleri","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1242\/jcs.199463","article-title":"Caught in the act-protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease","volume":"130","author":"Thomas","year":"2017","journal-title":"J. Cell Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S0092-8674(02)01162-5","article-title":"HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway","volume":"111","author":"Blagoveshchenskaya","year":"2002","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/sj.emboj.7600559","article-title":"PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis","volume":"24","author":"Simmen","year":"2005","journal-title":"EMBO J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/sj.emboj.7600566","article-title":"Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation","volume":"24","author":"Benzing","year":"2005","journal-title":"EMBO J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/s41467-024-44989-7","article-title":"iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity","volume":"15","author":"Rylaarsdam","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e104888","DOI":"10.15252\/embj.2020104888","article-title":"Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases","volume":"40","author":"Bonora","year":"2021","journal-title":"EMBO J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7964\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:30:00Z","timestamp":1760034600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7964"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,18]]},"references-count":65,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26167964"],"URL":"https:\/\/doi.org\/10.3390\/ijms26167964","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,18]]}}}