Abstract Introduction of a Novel Pathogenic Variant (c.1684G>A) in The SOX5 Gene Associated With Lamb–Shaffer Syndrome in a Family From North of Iran
,
Abstract
So far, different types of SOX5 variants have been reported in patients with LAMSHF syndrome, which are mainly clustered in the HMG domain. The LAMSHF syndrome has a broad variety of clinical manifestations such as developmental delay, speech delay, intellectual disability, and behavioral disturbances. In this article, we aim to present three cases with Lamb–Shaffer syndrome who are heterozygotes for a novel variant (c.1684G>A) in the SOX5 gene in a family from the north of Iran.A 38-year-old male case with moderate mental retardation and strabismus, with a head circumference size of 56 cm, was tested for genetic diagnosis. The results of whole- exome sequencing (WES) indicated the c.1684G>A pathogenic variant (NM_006940.6) in the SOX5 gene in a heterozygote state. Family analysis showed that the proband’s sister and father, who have similar symptoms, also carry the detected variant.Like the previous cases, the presented cases with a missense variant in the HMG- domain also have a mild phenotype. The introduction of new patients, especially with new pathogenic variants, is fundamental to increasing our knowledge about the disease and possible genotype–phenotype correlations.
[1] Kamachi Y, Kondoh H. Sox proteins: regulators of cell fate specifi- cation and differentiation. Development. 2013;140(20):4129- 44.https://doi.org/10.1242/dev.091793
[2] Bowles J, Schepers G, Koopman P. Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol. 2000;227(2):239-55.https:// doi.org/10.1006/dbio.2000.9883
[3] Ji EH, Kim J. SoxD transcription factors: multifaceted players of neural development. Int J Stem Cells. 2016;9(1):3-8.https:// doi.org/10.15283/ijsc.2016.9.1.3
[4] Zawerton A, Mignot C, Sigafoos A, Blackburn PR, Haseeb A, McWalter K, et al. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmen- tal disorder due to SOX5 haploinsufficiency. Genet Med. 2020;22(3):524-37.https://doi.org/10.1038/s41436-019- 0657-0
[5] Sim H, Argentaro A, Harley VR. Boys, girls and shuttling of SRY and SOX9. Trends Endocrinol Metab. 2008;19(6):213-22. https://doi.org/10.1016/j.tem.2008.04.002
[6] Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, et al. Mutations in the transcription factor gene SOX18 un- derlie recessive and dominant forms of hypotrichosis-lymph- edema-telangiectasia. Am J Hum Genet. 2003;72(6):1470-8. https://doi.org/10.1086/375614
[7] Zawerton A, Yao B, Yeager JP, Pippucci T, Haseeb A, Smith JD, et al. De novo SOX4 variants cause a neurodevelopmen- tal disease associated with mild dysmorphism. Am J Hum Genet. 2019;104(2):246-59.https://doi.org/10.1016/j. ajhg.2018.12.014
[8] Tsurusaki Y, Koshimizu E, Ohashi H, Phadke S, Kou I, Shiina M, et al. De novo SOX11 mutations cause Coffin-Siris syndrome. Nat Commun. 2014;5(1):1-7.https://doi.org/10.1038/ncom- ms5011
[9] Fukushi D, Yamada K, Suzuki K, Inaba M, Nomura N, Suzuki Y, et al. Clinical and genetic characterization of a patient with SOX5 haploinsufficiency caused by a de novo balanced re- ciprocal translocation. Gene. 2018;655:65-70.https://doi. org/10.1016/j.gene.2018.02.049
[10] Nesbitt A, Bhoj EJ, McDonald Gibson K, Yu Z, Denenberg E, Sarmady M, et al. Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presenta- tion with review of sox-related disorders. Am J Med Genet A. 2015;167(11):2548-54.https://doi.org/10.1002/ajmg.a.37221
[11] Lamb AN, Rosenfeld JA, Neill NJ, Talkowski ME, Blumenthal I, Girirajan S, et al. Haploinsufficiency of SOX5 at 12p12. 1 is as- sociated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Hum Mutat. 2012;33(4):728-40.https://doi.org/10.1002/ humu.22037
[12] Rosenfeld JA, Ballif BC, Torchia BS, Sahoo T, Ravnan JB, Schultz R, et al. Copy number variations associated with autism spec- trum disorders contribute to a spectrum of neurodevelop- mental disorders. Genet Med. 2010;12(11):694-702.https:// doi.org/10.1097/GIM.0b013e3181f0c5f3
[13] Lee RW, Bodurtha J, Cohen J, Fatemi A, Batista D. Deletion 12p12 involving SOX5 in two children with developmental de- lay and dysmorphic features. Pediatr Neurol. 2013;48(4):317- 20.https://doi.org/10.1016/j.pediatrneurol.2012.12.013
[14] Schanze I, Schanze D, Bacino CA, Douzgou S, Kerr B, Zenker M. Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intel- lectual disability. Eur J Med Genet. 2013;56(2):108-13.https:// doi.org/10.1016/j.ejmg.2012.11.001
[15] Zech M, Poustka K, Boesch S, Berutti R, Strom TM, Grisold W, et al. SOX5-null heterozygous mutation in a family with adult-on- set hyperkinesia and behavioral abnormalities. Case Rep Gen- et. 2017;2017.https://doi.org/10.1155/2017/2721615
[16] Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg E-J, de Vries P, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19(9):1194-6.https://doi.org/10.1038/ nn.4352
[17] Coe BP, Witherspoon K, Rosenfeld JA, Van Bon BW, Vulto-van Silfhout AT, Bosco P, et al. Refining analyses of copy number variation identifies specific genes associated with develop- mental delay. Nat Genet. 2014;46(10):1063-71.https://doi. org/10.1038/ng.3092
[2] Bowles J, Schepers G, Koopman P. Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol. 2000;227(2):239-55.https:// doi.org/10.1006/dbio.2000.9883
[3] Ji EH, Kim J. SoxD transcription factors: multifaceted players of neural development. Int J Stem Cells. 2016;9(1):3-8.https:// doi.org/10.15283/ijsc.2016.9.1.3
[4] Zawerton A, Mignot C, Sigafoos A, Blackburn PR, Haseeb A, McWalter K, et al. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmen- tal disorder due to SOX5 haploinsufficiency. Genet Med. 2020;22(3):524-37.https://doi.org/10.1038/s41436-019- 0657-0
[5] Sim H, Argentaro A, Harley VR. Boys, girls and shuttling of SRY and SOX9. Trends Endocrinol Metab. 2008;19(6):213-22. https://doi.org/10.1016/j.tem.2008.04.002
[6] Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, et al. Mutations in the transcription factor gene SOX18 un- derlie recessive and dominant forms of hypotrichosis-lymph- edema-telangiectasia. Am J Hum Genet. 2003;72(6):1470-8. https://doi.org/10.1086/375614
[7] Zawerton A, Yao B, Yeager JP, Pippucci T, Haseeb A, Smith JD, et al. De novo SOX4 variants cause a neurodevelopmen- tal disease associated with mild dysmorphism. Am J Hum Genet. 2019;104(2):246-59.https://doi.org/10.1016/j. ajhg.2018.12.014
[8] Tsurusaki Y, Koshimizu E, Ohashi H, Phadke S, Kou I, Shiina M, et al. De novo SOX11 mutations cause Coffin-Siris syndrome. Nat Commun. 2014;5(1):1-7.https://doi.org/10.1038/ncom- ms5011
[9] Fukushi D, Yamada K, Suzuki K, Inaba M, Nomura N, Suzuki Y, et al. Clinical and genetic characterization of a patient with SOX5 haploinsufficiency caused by a de novo balanced re- ciprocal translocation. Gene. 2018;655:65-70.https://doi. org/10.1016/j.gene.2018.02.049
[10] Nesbitt A, Bhoj EJ, McDonald Gibson K, Yu Z, Denenberg E, Sarmady M, et al. Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presenta- tion with review of sox-related disorders. Am J Med Genet A. 2015;167(11):2548-54.https://doi.org/10.1002/ajmg.a.37221
[11] Lamb AN, Rosenfeld JA, Neill NJ, Talkowski ME, Blumenthal I, Girirajan S, et al. Haploinsufficiency of SOX5 at 12p12. 1 is as- sociated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Hum Mutat. 2012;33(4):728-40.https://doi.org/10.1002/ humu.22037
[12] Rosenfeld JA, Ballif BC, Torchia BS, Sahoo T, Ravnan JB, Schultz R, et al. Copy number variations associated with autism spec- trum disorders contribute to a spectrum of neurodevelop- mental disorders. Genet Med. 2010;12(11):694-702.https:// doi.org/10.1097/GIM.0b013e3181f0c5f3
[13] Lee RW, Bodurtha J, Cohen J, Fatemi A, Batista D. Deletion 12p12 involving SOX5 in two children with developmental de- lay and dysmorphic features. Pediatr Neurol. 2013;48(4):317- 20.https://doi.org/10.1016/j.pediatrneurol.2012.12.013
[14] Schanze I, Schanze D, Bacino CA, Douzgou S, Kerr B, Zenker M. Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intel- lectual disability. Eur J Med Genet. 2013;56(2):108-13.https:// doi.org/10.1016/j.ejmg.2012.11.001
[15] Zech M, Poustka K, Boesch S, Berutti R, Strom TM, Grisold W, et al. SOX5-null heterozygous mutation in a family with adult-on- set hyperkinesia and behavioral abnormalities. Case Rep Gen- et. 2017;2017.https://doi.org/10.1155/2017/2721615
[16] Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg E-J, de Vries P, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19(9):1194-6.https://doi.org/10.1038/ nn.4352
[17] Coe BP, Witherspoon K, Rosenfeld JA, Van Bon BW, Vulto-van Silfhout AT, Bosco P, et al. Refining analyses of copy number variation identifies specific genes associated with develop- mental delay. Nat Genet. 2014;46(10):1063-71.https://doi. org/10.1038/ng.3092
| Files | ||
| Issue | Vol 8 No 6 (2023): November-December | |
| Section | Case Report(s) | |
| DOI | https://doi.org/10.18502/crcp.v8i6.16230 | |
| Keywords | ||
| LAMSHF syndrome SOX5 gene HMG-domain | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Amirfiroozy A, Jalali H, Khoshaeen A, Mahdavi MR, Mahdavi M. Abstract Introduction of a Novel Pathogenic Variant (c.1684G>A) in The SOX5 Gene Associated With Lamb–Shaffer Syndrome in a Family From North of Iran. CRCP. 2024;8(6):233-237.
