Curating genes at 20p13 to identify candidate genes for terminal microdeletions

Abstract

Purpose: Microdeletions are well-known drivers of genetic disorders. Generally, a few genes are identified as driver genes for the observed phenotypes in microdeletion carriers. In this study, we interrogated the 20p13 terminal region to identify candidate gene(s) primarily for the neurodevelopmental disorders in individuals with 20p13 terminal microdeletions.
Materials and methods: Publicly available information on gene functions, gene expressions, gene-disease relationships, and populational genomic data are used to identify genes within the terminal 2.5 Mb region of 20p13 that are tolerant or intolerant to deletions and loss-of-function variants.
Results: CSNK2A1 has the highest intolerance metrics to both deletion and loss-of-function variation among the 40 protein-coding genes within the terminal 2.5 Mb at 20p13, followed by SNPH when the rest of the genes are also evaluated by their gene functions and expression patterns.
Conclusion: We propose that CSNK2A1 is the main driver gene for the neurodevelopmental disorder/intellectual disability phenotypes in individuals with microdeletions encompassing genes within the terminal 2.5 Mb at 20p13 region.

Keywords

• CSNK2A1
• microarray
• SNPH
• NGS

Terminal 20p13 delesyonlarına aday genleri tanımlamak

Abstract

Amaç: Mikrodelesyonların genetik sendromlara yol açtığı bilinmektedir. Genellikle bir veya iki gen, gözlenen fenotiplerin ana nedeni olarak öne çıkarılır. Bu çalışmada, 20p13 mikrodelesyonu olan bireylerdeki fenotiplere yol açan major genleri tanımlamak amacıyla 20p13 terminal bölgesini araştırdık.
Gereç ve yöntem: 20p13’ün terminal 2.5 Mb bölgesi içinde delesyonlara toleranslı ve toleranssız genleri belirlemek amacıyla gen fonksiyonları, gen ekspresyonu ve gen–hastalık ilişkisi bilgileri ile delesyonlar ve fonksiyon kaybı varyantlarına ilişkin popülasyon verileri kullanılmıştır.
Bulgular: CSNK2A1 20p13’ün terminal 2.5 Mb bölgesi içinde yer alan 40 protein-kodlayan gen arasında en yüksek intolerans skorlarına sahip gendir ve onu SNPH takip etmektedir.
Sonuç: 20p13’ün terminal 2.5 Mb bölgesi içindeki genleri kapsayan mikrodelesyonlara sahip bireylerde görülen nörogelişimsel ve davranışsal bozukluk fenotiplerinin ana sürücü geninin CSNK2A1 olduğunu öne sürüyoruz.

Keywords

• CSNK2A1
• SNPH
• Mikrodizin
• NGS

References

1. Okur V, Cho MT, Henderson L, et al. De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features. Hum Genet. 2016;135(7):699-705. doi:10.1007/s00439-016-1661-y
2. Bagatelas ED, Khan MM, Rushing GV. OCNDS core features are conserved across variants, with loop-region mutations driving greater symptom burden. Front Hum Neurosci. 2025;19:1589897. doi:10.3389/fnhum.2025.1589897
3. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-443. doi:10.1038/s41586-020-2308-7
4. Foreman J, Perrett D, Mazaika E, Hunt SE, Ware JS, Firth HV. DECIPHER: improving genetic diagnosis through dynamic integration of genomic and clinical data. Annu Rev Genomics Hum Genet. 2023;24:151-176. doi:10.1146/annurev-genom-102822-100509
5. Chen S, Francioli LC, Goodrich JK, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625(7993):92-100. doi:10.1038/s41586-023-06045-0
6. Collins RL, Glessner JT, Porcu E, et al. A cross-disorder dosage sensitivity map of the human genome. Cell. 2022;185(16):3041-3055.e25. doi:10.1016/j.cell.2022.06.036
7. Perez G, Barber GP, Benet Pages A, et al. The UCSC Genome Browser database: 2025 update. Nucleic Acids Res. 2025;53(D1):D1243-D1249. doi:10.1093/nar/gkae974
8. Tooley M, Lynch D, Bernier F, et al. Cerebro-costo-mandibular syndrome: Clinical, radiological, and genetic findings. Am J Med Genet A. 2016;170A(5):1115-1126. doi:10.1002/ajmg.a.37587

9. Lieb A, Thaler G, Fogli B, et al. Functional characterization of spinocerebellar ataxia associated dynorphin A mutant peptides. Biomedicines. 2021;9(12). doi:10.3390/biomedicines9121882
10. Manini A, Bocci T, Migazzi A, et al. A case report of late-onset cerebellar ataxia associated with a rare p.R342W TGM6 (SCA35) mutation. BMC Neurol. 2020;20(1):408. doi:10.1186/s12883-020-01964-1
11. Guo YC, Lin JJ, Liao YC, Tsai PC, Lee YC, Soong BW. Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization. Neurology. 2014;83(17):1554-1561. doi:10.1212/WNL.0000000000000909
12. Liegel RP, Handley MT, Ronchetti A, et al. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013;93(6):1001-1014. doi:10.1016/j.ajhg.2013.10.011
13. Hozhabri H, Talebi M, Mehrjardi MYV, De Luca A, Dehghani M. Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran. Am J Med Genet A. 2020;182(5):957-961. doi:10.1002/ajmg.a.61543
14. Abdel Hamid MS, Abdel Ghafar SF, Ismail SR, et al. Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights. Clin Genet. 2020;98(5):445-456. doi:10.1111/cge.13825
15. Kang JS, Tian JH, Pan PY, et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell. 2008;132(1):137-148. doi:10.1016/j.cell.2007.11.024
16. Yamao T, Noguchi T, Takeuchi O, et al. Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1. J Biol Chem. 2002;277(42):39833-39839. doi:10.1074/jbc.M203287200
17. Toth AB, Terauchi A, Zhang LY, et al. Synapse maturation by activity-dependent ectodomain shedding of SIRPα. Nat Neurosci. 2013;16(10):1417-1425. doi:10.1038/nn.3516
18. Liu J, Li Y, Andersson HC, Upadia J. Subtelomeric microdeletion in chromosome 20p13 associated with short stature. Clin Case Rep. 2024;12(6):e8927. doi:10.1002/ccr3.8927
19. An Y, Amr SS, Torres A, et al. SOX12 and NRSN2 are candidate genes for 20p13 subtelomeric deletions associated with developmental delay. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(8):832-840. doi:10.1002/ajmg.b.32187
20. Fang HH, Liu SY, Wang YF, Chiang CM, Liu CC, Lin CM. Phenotypic features of a microdeletion in chromosome band 20p13: A case report and review of the literature. Mol Genet Genomic Med. 2019;7(7):e00739. doi:10.1002/mgg3.739
21. Jezela Stanek A, Kucharczyk M, Pelc M, Gutkowska A, Krajewska Walasek M. 1.15 Mb microdeletion in chromosome band 20p13 associated with moderate developmental delay-additional case and data’s review. Am J Med Genet A. 2013;161A(1):172-178. doi:10.1002/ajmg.a.35654
22. Moutton S, Rooryck C, Toutain J, et al. Dysmorphic features in subtelomeric 20p13 deletion excluding JAG1: a recognizable microdeletion phenotype? Eur J Med Genet. 2012;55(2):151-155. doi:10.1016/j.ejmg.2011.12.009
23. Martin MM, Vanzo RJ, Sdano MR, Baxter AL, South ST. Mosaic deletion of 20pter due to rescue by somatic recombination. Am J Med Genet A. 2016;170A(1):243-248. doi:10.1002/ajmg.a.37407
24. McGill AK, Pastore MT, Herman GE, Alliman S, Rosenfeld JA, Weaver DD. A tale of two deletions: a report of two novel 20p13 --> pter deletions. Am J Med Genet A. 2010;152A(4):1000-1007. doi:10.1002/ajmg.a.33339
25. Yener C, Sayın C, İnan C, et al. Prenatal diagnosis of 20p13 microdeletion syndrome. Taiwan J Obstet Gynecol. 2021;60(2):350-354. doi:10.1016/j.tjog.2021.01.015
26. Chung W, Okur V. Okur-Chung Neurodevelopmental Syndrome (OCNDS). In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews®. University of Washington, Seattle; 1993.