

Clinical and genetic heterogeneity of SATB2-associated syndrome
https://doi.org/10.21508/1027-4065-2024-69-6-27-33
Abstract
Marfan syndrome (OMIM #154700) is an autosomal dominantly inherited connective tissue disorder caused by mutations in the FBN1 gene and is marked by significant clinical variability, including cardiovascular manifestations. The causes of this variability remain inadequately studied, and relatively few genotype-phenotype correlations have been identified to date. In this study, we examined 66 children with Marfan syndrome to identify genotype-phenotype correlations. Biochemical, functional, and genetic research methods were employed, confirming a positive correlation between ectopia lentis and missense variants in the FBN1 gene. Additionally, in our cohort, patients with loss-of-function (LoF) mutations, compared to those with missense mutations, statistically showed larger aortic dimensions, earlier onset of foot deformities, marked dolichostenomelia, a higher frequency of elbow contractures, chest deformities, and aortic dilation. Patients with missense variants involving cysteine loss, as opposed to those without cysteine involvement, demonstrated an earlier onset of spinal deformity, higher natriuretic peptide (NT-proBNP) levels, larger aortic sizes, increased prevalence of chest deformities, particularly carinatum, ectopia lentis, and a greater propensity for osteoporosis. Patients with mutations in exons 11 to 20, compared to those with mutations in other exons, were less likely to exhibit pectus carinatum and aortic dilation and had less pronounced dolichostenomelia. Patients with mutations in exons 51 to 66, regardless of mutation type, were less likely to present with ectopia lentis. Thus, based on an analysis of genotype-phenotype correlations in a cohort of 66 children with Marfan syndrome, we identified several statistically significant correlations between phenotypic features of Marfan syndrome and mutation type and location within the FBN1 gene. This study confirmed that stable genotype-phenotype correlations are increasingly important for understanding clinical variability and for predicting disease severity.
About the Authors
S. E. NagievaRussian Federation
Moscow
N. A. Semenova
Russian Federation
Moscow
A. R. Morgul
Russian Federation
Moscow
Zh. G. Markova
Russian Federation
Moscow
T. I. Yanova
Russian Federation
Moscow
N. A. Vorobyov
Russian Federation
Moscow
O. S. Groznova
Russian Federation
Moscow
M. V. Vorontsova
Russian Federation
Moscow
N. A. Bodunova
Russian Federation
Moscow
References
1. Zarate Y.A., Fish J.L. SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. Am J Med Genet A 2017; 173(2): 327–337. DOI: 10.1002/ajmg.a.38022
2. Bengani H., Handley M., Alvi M., Ibitoye R., Lees M., Lynch S.A. et al. Clinical and molecular consequences of disease-associated de novo mutations in SATB2. Genet Med 2017; 19(8): 900–908. DOI: 10.1038/gim.2016.211
3. Zarate Y.A., Kalsner L., Basinger A., Jones J.R., Li C., Szybowska M. et al. Genotype and phenotype in 12 additional individuals with SATB2-associated syndrome. Clin Genet 2017; 92(4): 423–429. DOI: 10.1111/cge.12982
4. Glass I.A., Swindlehurst C.A., Aitken D.A., McCrea W., Boyd E. Interstitial deletion of the long arm of chromosome 2 with normal levels of isocitrate dehydrogenase. J Med Genet 1989; 26(2): 127–130. DOI: 10.1136/jmg.26.2.127
5. Van Buggenhout G., Van Ravenswaaij-Arts C., Mc Maas N., Thoelen R., Vogels A., Smeets D. et al. The del(2)(q32.2q33) deletion syndrome defined by clinical and molecular characterization of four patients. Eur J Med Genet 2005; 48(3): 276–289. DOI: 10.1016/j.ejmg.2005.05.005
6. de Ravel T.J., Balikova I., Thiry P., Vermeesch J.R., Frijns J.P. Another patient with a de novo deletion further delineates the 2q33.1 microdeletion syndrome. Eur J Med Genet 2009; 52(2–3): 120–122. DOI: 10.1016/j.ejmg.2009.01.002
7. Urquhart J., Black G.C., Clayton-Smith J. 4.5 Mb microdeletion in chromosome band 2q33.1 associated with learning disability and cleft palate. Eur J Med Genet 2009; 52(6): 454– 457. DOI: 10.1016/j.ejmg.2009.06.003
8. Balasubramanian M., Smith K., Basel-Vanagaite L., Feingold M.F., Brock P., Gowans G.C. et al. Case series: 2q33.1 microdeletion syndrome–-further delineation of the phenotype. J Med Genet 2011; 48(5): 290–298. DOI: 10.1136/jmg.2010.084491
9. Mc Cormack A., Taylor J., Gregersen N., George A.M., Love D.R. Delineation of 2q32q35 deletion phenotypes: two apparent «proximal» and «distal» syndromes. Case Rep Genet 2013; 2013: 823451. DOI: 10.1155/2013/823451
10. Yu N., Shin S., Lee K.A. First Korean case of SATB2-associated 2q32–q33 microdeletion syndrome. Ann Lab Med 2015; 35(2): 275–278. DOI: 10.3343/alm.2015.35.2.275
11. Zhu Y.Y., Sun G.L., Yang Z.L. SATB2-associated syndrome caused by a novel SATB2 mutation in a Chinese boy: A case report and literature review. World J Clin Cases 2021; 9(21): 6081–6090. DOI: 10.12998/wjcc.v9.i21.6081
12. Liedén A., Kvarnung M., Nilssson D., Sahlin E., Lundberg E.S. Intragenic duplication–-a novel causative mechanism for SATB2-associated syndrome. Am J Med Genet A 2014; 164A(12): 3083–3087. DOI: 10.1002/ajmg.a.36769
13. Grelet M., Mortreux J., Alazard E., Sigaudy S., Philip N., Missirian C. SATB2-associated syndrome: first report of a gonadal and somatic mosaicism for an intragenic copy number variation. Clin Dysmorphol 2019; 28(4): 205–210. DOI: 10.1097/MCD.0000000000000293
14. Qian Y, Liu J, Yang Y, Chen M., Jin C., Chen P. et al. Paternal Low-Level Mosaicism-Caused SATB2-Associated Syndrome. Front Genet 2019; 10: 630. DOI: 10.3389/fgene.2019.00630
15. Leoyklang P., Suphapeetiporn K., Srichomthong C., Tongkobpetch S., Fietze S., Dorward H. et al. Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene. Hum Genet 2013; 132(12): 1383–1393. DOI: 10.1007/s00439–013–1345–9
16. Döcker D., Schubach M., Menzel M., Munz M., Spaich C., Biskup S., Bartholdi D. Further delineation of the SATB2 phenotype. Eur J Hum Genet 2014; 22(8): 1034–1039. DOI: 10.1038/ejhg.2013.280
17. Machado R.D., Pauciulo M.W., Fretwell N., Veal C., Thomson J.R., Vilariño Güell C. et al. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium. Genomics 2000; 68(2): 220– 228. DOI: 10.1006/geno.2000.6291
18. Dobreva G., Chahrour M., Dautzenberg M., Chirivella L., Kanzler B., Fariñas I. et al. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell 2006; 125(5): 971–986. DOI: 10.1016/j.cell.2006.05.012
19. Krasnoshekova E.I., Zykin P.A., Tkachenko L.A., Kozubenko E.A., Kostin N.A., Tsvetkov E.A. et al. Features of differentiation of the human cerebral cortex during the second trimester of gestation. Zhurnal vysshei nervnoi deyatel’nosti im. I.P. Pavlova. 2021; 71(5): 605–619. (in Russ.) DOI: 10.31857/S0044467721040043
20. Dowrey T., Schwager E.E., Duong J., Merkuri F., Zarate Y.A., Fish J.L. Satb2 regulates proliferation and nuclear integrity of pre-osteoblasts. Bone 2019; 127: 488–498. DOI: 10.1016/j.bone.2019.07.017
21. Ryzhkova O.P., Kardymon O.L., Prohorchuk E.B., Konovalov F.A., Maslennikov A.B., Stepanov V.A. et al. Guidelines for the interpretation of massive parallel sequencing variants (update 2018, v2). Meditsinskaya genetika 2019; 18(2): 3–23. (in Russ.) DOI: 10.25557/2073–7998.2019.02.3–23
Review
For citations:
Nagieva S.E., Semenova N.A., Morgul A.R., Markova Zh.G., Yanova T.I., Vorobyov N.A., Groznova O.S., Vorontsova M.V., Bodunova N.A. Clinical and genetic heterogeneity of SATB2-associated syndrome. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2024;69(6):27-33. (In Russ.) https://doi.org/10.21508/1027-4065-2024-69-6-27-33