Genetics Corner: A New Case of Rubinstein-Taybi Syndrome with a Novel Variant in the CREBBP Gene Detected through Whole Exome Sequencing

/

, , ,

Hua Wang, M.D., Ph.D., Ann Ly, GC, MSc.

Abstract:

Rubinstein-Taybi syndrome (RSTS), an autosomal-dominant neurodevelopmental disorder affecting 1 in 125,000 newborns, is characterized by intellectual disability, growth retardation, facial dysmorphisms, and skeletal abnormalities. RSTS results from mutations in epigenetic machinery genes: CREBBP (~60%) or its homologous EP300 (~10%). Up to 30% of patients lack identified causative mutations, complicating early diagnosis due to phenotypic overlap with other syndromes. Here, we report a new RSTS case in an infant with atypical presentation. Whole-exome sequencing at 20 months revealed a de novo heterozygous pathogenic variant in CREBBP, c.6067C>T (p.Gln2023*), establishing the diagnosis. This case introduces a new CREBBP gene variant, illustrating the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus. High WES diagnostic rates emphasize its utility in cases with challenging phenotypes spanning distinct syndromes.

[READ CASE STUDY BELOW]

References:

  1. Milani D, Manzoni FM, Pezzani L, Ajmone P, Gervasini C, Menni F, et al. Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management. Ital J Pediatr. 2015;41:4. Epub 2015/01/21. doi: 10.1186/s13052-015-0110-1. PubMed PMID: 25599811; PubMed Central PMCID: PMCPMC4308897.
  2. Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child. 1963;105:588-608. Epub 1963/06/01. doi: 10.1001/archpedi.1963.02080040590010. PubMed PMID: 13983033.
  3. Spena S, Gervasini C, Milani D. Ultra-Rare Syndromes: The Example of Rubinstein-Taybi Syndrome. J Pediatr Genet.2015;4(3):177–86. Epub 2016/09/13. doi: 10.1055/s-0035-1564571. PubMed PMID: 27617129; PubMed Central PMCID: PMCPMC4918723.
  4. Yumul RCR, Chiong MAD. Rubinstein-Taybi Syndrome in a Filipino Infant with a Novel CREBBP Gene Pathogenic Variant. Case Rep Genet. 2022;2022:3388879. Epub 2022/06/01. doi: 10.1155/2022/3388879. PubMed PMID: 35637708; PubMed Central PMCID: PMCPMC9148230.
  5. 5. Negri G, Magini P, Milani D, Crippa M, Biamino E, Piccione M, et al. Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders. Hum Genet. 2019;138(3):257–69. Epub 2019/02/27. doi: 10.1007/s00439-019-01985-y. PubMed PMID: 30806792; PubMed Central PMCID: PMCPMC6736609.
  6. Yu S, Wu B, Qian Y, Zhang P, Lu Y, Dong X, et al. Clinical exome sequencing identifies novel CREBBP variants in 18 Chinese Rubinstein-Taybi Syndrome kids with high frequency of polydactyly. Mol Genet Genomic Med. 2019;7(12):e1009. Epub 2019/10/23. doi: 10.1002/mgg3.1009. PubMed PMID: 31637876; PubMed Central PMCID: PMCPMC6900364.
  7. Roelfsema JH, White SJ, Ariyürek Y, Bartholdi D, Niedrist D, Papadia F, et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet. 2005;76(4):572– 80. Epub 2005/02/12. doi: 10.1086/429130. PubMed PMID: 15706485; PubMed Central PMCID: PMCPMC1199295.
  8. Van Gils J, Magdinier F, Fergelot P, Lacombe D. Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder. Genes (Basel). 2021;12(7). Epub 2021/07/03. doi: 10.3390/genes12070968. PubMed PMID: 34202860; PubMed Central PMCID: PMCPMC8303114.
  9. Stevens CA. Rubinstein-Taybi Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®️). Seattle (WA): University of Washington, Seattle
    Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.
  10. Miller RW, Rubinstein JH. Tumors in Rubinstein-Taybi syndrome. Am J Med Genet. 1995;56(1):112–5. Epub 1995/03/13. doi: 10.1002/ajmg.1320560125. PubMed PMID: 7747773.
  11. Tekendo-Ngongang C, Owosela B, Fleischer N, Addissie YA, Malonga B, Badoe E, et al. Rubinstein-Taybi syndrome indiverse populations. Am J Med Genet A. 2020;182(12):2939–50. Epub 2020/09/29. doi: 10.1002/ajmg.a.61888. PubMed PMID: 32985117.
  12. Alari V, Russo S, Terragni B, Ajmone PF, Sironi A, Catusi I, et al. iPSC-derived neurons of CREBBP- and EP300-mutated Rubinstein-Taybi syndrome patients show morphological alterations and hypoexcitability. Stem Cell Res. 2018;30:130–40. Epub 2018/06/09. doi: 10.1016/j.scr.2018.05.019. PubMed PMID: 29883886.
  13. Lopez-Atalaya JP, Valor LM, Barco A. Epigenetic factors in intellectual disability: the Rubinstein-Taybi syndrome as a paradigm of neurodevelopmental disorder with epigenetic origin. Prog Mol Biol Transl Sci. 2014;128:139–76. Epub 2014/11/21. doi: 10.1016/b978-0-12-800977-2.00006-1. PubMed PMID: 25410544.
  14. Al-Qattan MM, Rahbeeni ZA, Al-Hassnan ZN, Jarman A, Rafique A, Mahabbat N, et al. Chromosome 16p13.3 Contiguous Gene Deletion Syndrome including the SLX4, DNASE1, TRAP1, and CREBBP Genes Presenting as a Relatively Mild Rubinstein-Taybi Syndrome Phenotype: A Case Report of a Saudi Boy. Case Rep Genet. 2020;2020:6143050. Epub 2020/03/18. doi: 10.1155/2020/6143050. PubMed PMID: 32181026; PubMed Central PMCID: PMCPMC7064822.
  15. Banka S, Sayer R, Breen C, Barton S, Pavaine J, Sheppard SE, et al. Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP. Am J Med Genet A. 2019;179(6):1058– 62. Epub 2019/03/21. doi: 10.1002/ajmg.a.61131. PubMed PMID: 30892814.
  16. Wang Q, Wang C, Wei WB, Rong WN, Shi XY. A novel CREBBP mutation and its phenotype in a case of Rubinstein-Taybi syndrome. BMC Med Genomics. 2022;15(1):182. Epub 2022/08/20. doi: 10.1186/s12920-022-01335-4. PubMed PMID: 35986282; PubMed Central PMCID: PMCPMC9389776.

Acknowlegement: We express gratitude for the patient’s family’s generous consent to publish both the case details and accompanying photos. No conflicts of interest are identified.

nt-23-12-165-170Download