Mappatura delle correlazioni genotipo-fenotipo nelle sindromi genetiche rare con manifestazioni a carico della testa e del collo: A Scoping Review
Barra laterale dell'articolo
Contenuto principale dell'articolo
Abstract
Introduzione:
Le rare sindromi genetiche che colpiscono la testa e il collo si presentano frequentemente con anomalie craniofacciali e osteodisplastiche caratteristiche. Comprendere le correlazioni genotipo-fenotipo in queste patologie è fondamentale per una diagnosi accurata, una prognosi precisa e interventi mirati. Questa revisione esplorativa mappa sistematicamente le evidenze molecolari e fenotipiche relative a sindromi monogeniche, multilocus e ultra-rare.
Metodi:
Una ricerca esaustiva ha identificato 35 studi pubblicati tra il 2005 e il 2025, inclusi case report, serie di casi, studi di coorte e revisioni. I dati sono stati sintetizzati in forma narrativa e integrati con confronti tabellari per valutare le associazioni tra geni, tipi di mutazione e fenotipi craniofacciali. Sono state riassunte le evidenze funzionali e la presenza di varianti di significato incerto (VUS).
Risultati:
Sindromi ben caratterizzate, come la sindrome di Apert (FGFR2), la sindrome branchio-oculo-facciale (TFAP2A) e la sindrome di Axenfeld-Rieger (PITX2, FOXC1), hanno dimostrato solide correlazioni genotipo-fenotipo, con varianti patogene ricorrenti costantemente associate a caratteristiche quali craniosinostosi, ipoplasia del mesoviso, palatoschisi e micrognazia. I disturbi multilocus e oligogenici hanno rivelato fenotipi osteodisplastici e craniofacciali sovrapposti, evidenziando gli effetti additivi delle varianti su vie metaboliche interagenti.
Le varianti di significato incerto (VUS) sono state frequentemente riscontrate in fattori di trascrizione, regolatori dello splicing e geni strutturali (SOX9, COL2A1, EFTUD2, SNRPB), spesso raggruppandosi con fenotipi specifici ma senza validazione funzionale. I test funzionali, inclusi studi di trascrizione/splicing in vitro, modelli murini e di pesce zebra e modellizzazione molecolare, hanno rafforzato l'interpretazione delle varianti laddove disponibili. Nell'ambito delle diverse sindromi, è stata osservata una convergenza fenotipica in un insieme limitato di percorsi di sviluppo, suggerendo meccanismi comuni alla base del dismorfismo craniofacciale nonostante l'eterogeneità genetica.
Conclusione:
Questa revisione delinea lo spettro delle relazioni genotipo-fenotipo nelle rare sindromi craniofacciali, ponendo l'accento sui disturbi ben caratterizzati con firme molecolari trattabili e evidenziando le lacune nelle condizioni ultra-rare o multilocus. L'integrazione della genomica ad alta risoluzione con test funzionali standardizzati e coorti eterogenee è essenziale per affinare l'interpretazione delle varianti, migliorare la traslazione clinica e promuovere la medicina di precisione nella genetica craniofacciale.
Downloads
Dettagli dell'articolo
Questo lavoro è fornito con la licenza Creative Commons Attribuzione - Non commerciale 4.0 Internazionale.
Riferimenti bibliografici
Jadico, S.K., Young, D.A., Huebner, A., Edmond, J.C., Pollock, A.N., McDonald-McGinn, D.M., Li, Y.-J., Zackai, E.H. and Young, T.L. (2006). Ocular abnormalities in Apert syndrome: Genotype/phenotype correlations with fibroblast growth factor receptor type 2 mutations. Journal of American Association for Pediatric Ophthalmology and Strabismus, [online] 10(6), pp.521–527. doi:https://doi.org/10.1016/j.jaapos.2006.07.012.
Pauws, E., Peskett, E., Boissin, C., Hoshino, A., Mengrelis, K., Carta, E., Abruzzo, M., Lees, M., Moore, G., Erickson, R. and Stanier, P. (2013). X linked CHARGE like Abruzzo Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations. Clinical Genetics, [online] 83(4), pp.352–358. doi:https://doi.org/10.1111/j.1399-0004.2012.01930.x.
Piranit Nik Kantaputra, Prapai Dejkhamron, Worrachet Intachai, Chumpol Ngamphiw, Kawasaki, K., Atsushi Ohazama, Suttichai Krisanaprakornkit, Olsen, B., Sissades Tongsima and Ketudat, J.R. (2020). Juberg Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2. European Journal of Orthodontics, [online] 43(1), pp.45–50. doi:https://doi.org/10.1093/ejo/cjaa023.
Petit, F., F. Escande, Jourdain, A.S., N. Porchet, Amiel, J., Doray, B., M.A. Delrue, Flori, E., Kim, C.A., Marlin, S., Robertson, S.P., S. ManouvrierHanu and M. HolderEspinasse (2013). Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clinical Genetics, [online] 86(3), pp.246-251. doi:https://doi.org/10.1111/cge.12259.
Al-Qattan, M.M. and Almohrij, S.A. (2022). The Pathogenesis of Pierre Robin Sequence through a Review of SOX9 and Its Interactions. Plastic & Reconstructive Surgery Global Open, [online] 10(4), pp.e4241–e4241. doi:https://doi.org/10.1097/gox.0000000000004241.
Zahra Motahari, Moody, S.A., Maynard, T.M. and LaMantia, A.-S. (2019). In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects? Journal of Neurodevelopmental Disorders, [online] 11(1). doi:https://doi.org/10.1186/s11689-019-9267-z.
Gogoll, L., Steindl, K., Joset, P., Zweier, M., Baumer, A., Gerth Kahlert, C., Tutschek, B. and Rauch, A. (2021). Confirmation of Ogden syndrome as an X linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature. American Journal of Medical Genetics Part A, [online] 185(8), pp.2546 2560. doi:https://doi.org/10.1002/ajmg.a.62351.
Iovino, E., Luca Scapoli, Palmieri, A., Rossella Sgarzani, Nouri, N., Agnese Pellati, Carinci, F., Seri, M., Tommaso Pippucci and Martinelli, M. (2023). Ultra Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non Syndromic Cleft Palate Only. Biomolecules, [online] 13(2), pp.236 236. doi:https://doi.org/10.3390/biom13020236.
Spela Mirosevic, Khandelwal, S., Susjan, P., zakelj,N., Gosar, D., Forstneric, V., Dusko Lainscek, Jerala, R. and Damjan Osredkar 2022 Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature. International Journal of Molecular Sciences, [online] 23(20), pp.12564–12564. doi:https://doi.org/10.3390/ijms232012564.
Miller, S.F., Weinberg, S.M., Nidey, N.L., Defay, D.K., Marazita, M.L., Wehby, G.L. and Moreno, L.M. (2014). Exploratory genotype phenotype correlations of facial form and asymmetry in unaffected relatives of children with non syndromic cleft lip and or palate. Journal of Anatomy, [online] 224(6), pp.688–709. doi:https://doi.org/10.1111/joa.12182.
Liu, Z-, Zhouu D. Wang C Zheng B. Yan Q. Zhou W anda Wang G. (2025) Genetic Insights Into Craniosynostosis Identification of Novel IL11RA Variants in Chinese Pediatric Patients. Molecular Genetics & Genomic Medicine, [online] 13(5). doi:https://doi.org/10.1002/mgg3.70106.
Xu, Y., Zhang, X., Lu, W., Xiao, Y., Ma, X., Chen, L. and Dong, Z. (2025). A novel EFTUD2 splicing variant causing mandibulofacial dysostosis with microcephaly: a case report. Translational Pediatrics, [online] 14(6), pp.1336–1343. doi:https://doi.org/10.21037/tp-2024-587.
Christos Yapijakis, Iphigenia Gintoni, Myrsini Chamakioti, Koniari, E., Papanikolaou, E., Kassi, E., Dimitrios Vlachakis and Chrousos, G.P. (2025). Genotype Phenotype Correlation Insights in a Rare Case Presenting with Multiple Osteodysplastic Syndromes. Genes, [online] 16(8), pp.871–871. doi:https://doi.org/10.3390/genes16080871.
Le Goff C. Michot C and Cormier Daire V (2014). Myhre syndrome. Clinical Genetics, [online] 85(6), pp.503-513. doi:https://doi.org/10.1111/cge.12365.
A. Mitrakos, K. Kekou F.N. Tilemis, M. Svingou, G. Papadomas, C. Sofocleous J. Traeger Synodinos and ;. Tzietis (2024) Nablus mask like facial syndrome: Report of an atypical case with 8q21.3q22.1 deletion. American Journal of Medical Genetics Part A, [online] 194(12). doi:https://doi.org/10.1002/ajmg.a.63826.
Meshcheryakova, T.I., Zinchenko, R.A., Vasilyeva, T.A., Marakhonov, A.V., Zhylina, S.S., Petrova, N.V., Kozhanova, T.V., Belenikin, M.S., Petrin, A.N. and Mutovin, G.R. (2015). A Clinical and Molecular Analysis of Branchio Oculo Facial Syndrome Patients in Russia Revealed New Mutations in TFAP2A. Annals of Human Genetics, [online] 79(2), pp.148–152. doi:https://doi.org/10.1111/ahg.12098.
Sato, T., Samura, O., Kato, N., Taniguchi, K., Takahashi, K., Ito, Y., Aoki, H., Kobayashi, M., Migita, O., Okamoto, A. and Hata, K. (2018). Novel TFAP2A mutation in a Japanese family with Branchio oculo facial syndrome. Human Genome Variation, [online] 5(1). doi:https://doi.org/10.1038/s41439-018-0004-z.
Luo, F., Lu, M., Zhao, L. and Zhou, P. (2023). A neonatal case report of branchiooculofacial syndrome caused by a novel mutation in the TFAP2A gene and literature review. Medicine, [online] 102(44), p.e34962. doi:https://doi.org/10.1097/md.0000000000034962.
Castiglione, A., Melchionda, S., Carella, M., Trevisi, P., Bovo, R., Manara, R. and Martini, A. (2014). EYA1-related disorders: Two clinical cases and a literature review. International Journal of Pediatric Otorhinolaryngology, [online] 78(8), pp.1201–1210. doi:https://doi.org/10.1016/j.ijporl.2014.03.032.
Sherlaw-Sturrock, C., Austin, T., Baptista, J., Gilmour, K. and Naik, S. (2022). Dysmorphism and immunodeficiency - One of the differential diagnoses is PAX1 related otofaciocervical syndrome type 2. European Journal of Medical Genetics, [online] 65(7), pp.104523–104523. doi:https://doi.org/10.1016/j.ejmg.2022.104523.
Gana, S., Valetto, A., Toschi, B., Sardelli, I., Cappelli, S., Peroni, D. and Bertini, V. (2019). Familial Interstitial 6q23.2 Deletion Including Eya4 Associated With Otofaciocervical Syndrome. Frontiers in Genetics, [online] 10. doi:https://doi.org/10.3389/fgene.2019.00650.
Bezerra, J., Oliveira, G., Soares, C., Cardoso, M., MAG , AD Luchessi, Silbiger, V., Fajardo, C., Oliveira, S. de, das, M., Hirata, R.,Rezende, A. de and Hirata, M. (2014).Genetic and nongenetic factors that increase the risk of nonsyndromic cleft lip and or palate development. Oral Diseases, [online] 21(3), pp.393–399. [online] 21(3), pp.393–399. doi:https://doi.org/10.1111/odi.12292.
Alghonemy, W.Y. and Gaber Ashmawy, M. (2025). Meta-analysis and systematic review for the genetic basis of cleft lip and palate. Journal of Oral Biology and Craniofacial Research, [online] 15(1), pp.146–152. doi:https://doi.org/10.1016/j.jobcr.2024.12.012.
Cheng, X., Du, F., Long, X. and Huang, J. (2023). Genetic Inheritance Models of Non-Syndromic Cleft Lip with or without Palate: From Monogenic to Polygenic. Genes, [online] 14(10), p.1859. doi:https://doi.org/10.3390/genes14101859.
Miller, S.F., Weinberg, S.M., Nidey, N.L., Defay, D.K., Marazita, M.L., Wehby, G.L. and Moreno Uribe, L.M. (2014). Exploratory genotype–phenotype correlations of facial form and asymmetry in unaffected relatives of children with non-syndromic cleft lip and/or palate. Journal of Anatomy, [online] 224(6), pp.688–709. doi:https://doi.org/10.1111/joa.12182.
E., C., Ahmed, M., Wang, Y., Wang, J., Wu, S. and Meng, Z. (2025). A Case of Trichorhinophalangeal Syndrome Caused by a Novel Heterozygous Nonsense Mutation in the TRPS1 Gene. Clinical Case Reports, [online] 13(8). doi:https://doi.org/10.1002/ccr3.70695.
Herlin, L.K., Herlin, M.K., Blechingberg, J., Rønholt, K., Graversen, L., Schmidt, S.A.J., Jørgensen, M.W., Hellfritzsch, M.B., Hald, J.D., Beck-Nielsen, S.S., Gjørup, H., Andersen, B.N., Gregersen, P.A. and Sommerlund, M. (2024). Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants. European Journal of Medical Genetics, [online] 69, p.104937. doi:https://doi.org/10.1016/j.ejmg.2024.104937.
Nikoletta Selenti, Tzetis, M., Braoudaki, M., Krinio Giannikou, Kitsiou-Tzeli, S. and Fryssira, H. (2015). An interstitial deletion at 8q23.1-q24.12 associated with Langer-Giedion syndrome/ Trichorhinophalangeal syndrome (TRPS) type II and Cornelia de Lange syndrome 4. Molecular Cytogenetics, [online] 8(1). doi:https://doi.org/10.1186/s13039-015-0169-9.
Zhang, Y., Chen, X., Wang, L., Sun, X. and Chen, Y. (2021). Heterogeneity of Axenfeld–Rieger Syndrome: Molecular and Clinical Findings in Chinese Patients. Frontiers in Genetics, [online] 12. doi:https://doi.org/10.3389/fgene.2021.732170.
Gong, X., Lei, X., Li, Z. and Xing, Y. (2025). Identification and functional study of a novel FOXC1 missense mutation in a Chinese family with Axenfeld–Rieger syndrome. Scientific Reports, [online] 15(1). doi:https://doi.org/10.1038/s41598-025-04872-x.
White, S., Taranath, A., Hanagandi, P., Taranath, D.A., To, M.-S., Souzeau, E., Siggs, O.M. and Craig, J.E. (2023). Neuroimaging Findings in Axenfeld-Rieger Syndrome: A Case Series. AJNR. American journal of neuroradiology, [online] 44(10), pp.1231–1235. doi:https://doi.org/10.3174/ajnr.A7995.
Zhou, L., Wang, X., An, J., Zhang, Y., He, M. and Tang, L. (2022). Genotype-phenotype association of PITX2 and FOXC1 in Axenfeld-Rieger syndrome. Experimental Eye Research, [online] 226, pp.109307–109307. doi:https://doi.org/10.1016/j.exer.2022.109307.
Keppler-Noreuil, K.M., Martinez-Agosto, J.A., Hudgins, L. and Carey, J.C. (2017). 37th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2016 Annual Meeting. American Journal of Medical Genetics Part A, [online] 173(8), pp.2007–2073. doi:https://doi.org/10.1002/ajmg.a.38229.
French, C. R. (2021). Mechanistic Insights into Axenfeld–Rieger Syndrome from Zebrafish foxc1 and pitx2 Mutants. International Journal of Molecular Sciences, 22(18), 10001–10001. https://doi.org/10.3390/ijms221810001
Yang, D., Jian, Z., Tang, C., Chen, Z., Zhou, Z., Zheng, L. and Peng, X. (2024). Zebrafish Congenital Heart Disease Models: Opportunities and Challenges. International Journal of Molecular Sciences, [online] 25(11), pp.5943–5943. doi:https://doi.org/10.3390/ijms25115943.
Jbi.global. (2024). Revised JBI Methodology for Systematic Reviews of Textual Evidence | JBI. [online] Available at: https://jbi.global/news/article/revised-jbi-methodology-systematic-reviews-textual-evidence [Accessed 18 Nov. 2025].