Microduplication of 7q36.3 encompassing the SHH long‑range regulator (ZRS) in a patient with triphalangeal thumb‑polysyndactyly syndrome and congenital heart disease

Liu,Zhenghua; Yin,Ni; Gong,Lianghui; Tan,Zhiping; Yin,Bangliang; Yang,Yifeng; Luo,Cheng

doi:10.3892/mmr.2016.6092

Microduplication of 7q36.3 encompassing the SHH long‑range regulator (ZRS) in a patient with triphalangeal thumb‑polysyndactyly syndrome and congenital heart disease

Authors:
- Zhenghua Liu
- Ni Yin
- Lianghui Gong
- Zhiping Tan
- Bangliang Yin
- Yifeng Yang
- Cheng Luo
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Affiliations: Department of Cardiothoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: December 29, 2016 https://doi.org/10.3892/mmr.2016.6092
Pages: 793-797
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triphalangeal thumb‑polysyndactyly syndrome (TPT‑PS) is an autosomal dominant disorder with complete penetrance and a variable expression consisting of opposable triphalangeal thumbs, duplication of the distal thumb phalanx, pre‑axial polydactyly and duplication of the big toes (hallux). The causative gene of TPT‑PS has been mapped to 7q36.3. Sonic hedgehog (SHH) expressed in the zone of polarizing activity (ZPA) has an important role in defining the anterior‑posterior axis and numbers of digits in limb bud development. Point mutation or duplication in the ZPA regulatory sequence (ZRS), a cis‑regulator of SHH, will lead to TPT‑PS. The present study describes a 1‑year‑old female congenital heart disease (CHD) patient with TPT‑PS phenotype. In this Han Chinese family with TPT‑PS, high resolution single nucleotide polymorphism array technology identiﬁed a novel 0.29 Mb duplication comprising ZRS at 7q36.3 where LMBR1 is located. Additionally, a novel deletion of 22q11.21 was detected in the proband with Tetralogy of Fallot. However, the parents and other relatives of the patient did not harbor this genomic lesion nor CHD. The ﬁndings supported the hypothesis that an increased copy number variation of ZRS is the genetic mechanism underlying the phenotype of TPT‑PS, and corroborated that 22q11.21 deletion is a genetic cause of CHD.

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1	Tsukurov O, Boehmer A, Flynn J, Nicolai JP, Hamel BC, Traill S, Zaleske D, Mankin HJ, Yeon H and Ho C: A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nat Genet. 6:282–286. 1994. View Article : Google Scholar : PubMed/NCBI
2	Hill RE: How to make a zone of polarizing activity: Insights into limb development via the abnormality preaxial polydactyly. Dev Growth Differ. 49:439–448. 2007. View Article : Google Scholar : PubMed/NCBI
3	Radhakrishna U, Blouin JL, Solanki JV, Dhoriani GM and Antonarakis SE: An autosomal dominant triphalangeal thumb: Polysyndactyly syndrome with variable expression in a large Indian family maps to 7q36. Am J Med Genet. 66:209–215. 1996. View Article : Google Scholar : PubMed/NCBI
4	Lettice LA, Horikoshi T, Heaney SJ, van Baren MJ, van der Linde HC, Breedveld GJ, Joosse M, Akarsu N, Oostra BA, Endo N, et al: Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci USA. 99:7548–7553. 2002. View Article : Google Scholar : PubMed/NCBI
5	Lettice LA, Heaney SJ, Purdie LA, Li L, De Beer P, Oostra BA, Goode D, Elgar G, Hill RE and de Graaff E: A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 12:1725–1735. 2003. View Article : Google Scholar : PubMed/NCBI
6	Sagai T, Masuya H, Tamura M, Shimizu K, Yada Y, Wakana S, Gondo Y, Noda T and Shiroishi T: Phylogenetic conservation of a limb-specific, cis-acting regulator of Sonic hedgehog (Shh). Mamm Genome. 15:23–34. 2004. View Article : Google Scholar : PubMed/NCBI
7	Gurnett CA, Bowcock AM, Dietz FR, Morcuende JA, Murray JC and Dobbs MB: Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. Am J Med Genet A. 143A:27–32. 2007. View Article : Google Scholar : PubMed/NCBI
8	Wang ZQ, Tian SH, Shi YZ, Zhou PT, Wang ZY, Shu RZ, Hu L and Kong X: A single C to T transition in intron 5 of LMBR1 gene is associated with triphalangeal thumb-polysyndactyly syndrome in a Chinese family. Biochem Biophys Res Commun. 355:312–317. 2007. View Article : Google Scholar : PubMed/NCBI
9	Al-Qattan MM, Al Abdulkareem I, Al Haidan Y and Al Balwi M: A novel mutation in the SHH long-range regulator (ZRS) is associated with preaxial polydactyly, triphalangeal thumb, and severe radial ray deficiency. Am J Med Genet A. 158A:2610–2615. 2012. View Article : Google Scholar : PubMed/NCBI
10	Klopocki E, Ott CE, Benatar N, Ullmann R, Mundlos S and Lehmann K: A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J Med Genet. 45:370–375. 2008. View Article : Google Scholar : PubMed/NCBI
11	Sun M, Ma F, Zeng X, Liu Q, Zhao XL, Wu FX, Wu GP, Zhang ZF, Gu B, Zhao YF, et al: Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer. J Med Genet. 45:589–595. 2008. View Article : Google Scholar : PubMed/NCBI
12	Luo C, Yang YF, Yin BL, Chen JL, Huang C, Zhang WZ, Wang J, Zhang H, Yang JF and Tan ZP: Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome. Am J Med Genet A. 158A:1918–1923. 2012. View Article : Google Scholar : PubMed/NCBI
13	Tan ZP, Huang C, Xu ZB, Yang JF and Yang YF: Novel ZFPM2/FOG2 variants in patients with double outlet right ventricle. Clin Genet. 82:466–471. 2012. View Article : Google Scholar : PubMed/NCBI
14	Masuya H, Sezutsu H, Sakuraba Y, Sagai T, Hosoya M, Kaneda H, Miura I, Kobayashi K, Sumiyama K, Shimizu A, et al: A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud. Genomics. 89:207–214. 2007. View Article : Google Scholar : PubMed/NCBI
15	Beckmann JS, Estivill X and Antonarakis SE: Copy number variants and genetic traits: Closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet. 8:639–646. 2007. View Article : Google Scholar : PubMed/NCBI
16	Sharpe J, Lettice L, Hecksher-Sorensen J, Fox M, Hill R and Krumlauf R: Identification of sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch. Curr Biol. 9:97–100. 1999. View Article : Google Scholar : PubMed/NCBI
17	Goodship J, Cross I, LiLing J and Wren C: A population study of chromosome 22q11 deletions in infancy. Arch Dis Child. 79:348–351. 1998. View Article : Google Scholar : PubMed/NCBI
18	Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O'Leary LA, Wong LY, Elixson EM, et al: A population-based study of the 22q11.2 deletion: Phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 112:101–107. 2003. View Article : Google Scholar : PubMed/NCBI
19	Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, et al: Role of TBX1 in human del22q11.2 syndrome. Lancet. 362:1366–1373. 2003. View Article : Google Scholar : PubMed/NCBI
20	Shprintzen RJ: Velo-cardio-facial syndrome: 30 Years of study. Dev Disabil Res Rev. 14:3–10. 2008. View Article : Google Scholar : PubMed/NCBI
21	Momma K: Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol. 105:1617–1624. 2010. View Article : Google Scholar : PubMed/NCBI