Genetic and phenotypic continuum of HOXA genes: A case with double HOXA9/HOXA13 mutations

Jaouadi,Hager; Theron,Alexis; Norscini,Giulia; Avierinos,Jean-François; Zaffran,Stéphane

doi:10.3892/mmr.2023.12946

Genetic and phenotypic continuum of HOXA genes: A case with double HOXA9/HOXA13 mutations

Authors:
- Hager Jaouadi
- Alexis Theron
- Giulia Norscini
- Jean-François Avierinos
- Stéphane Zaffran
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Affiliations: Marseille Medical Genetics, U1251, National Institute of Health and Medical Research (INSERM), School of Medicine, Aix Marseille University, 13005 Marseille, France, Department of Cardiology, Public Assistance‑Hospitals of Marseille, La Timone Hospital, 13005 Marseille, France
Published online on: January 27, 2023 https://doi.org/10.3892/mmr.2023.12946
Article Number: 59
Copyright: © Jaouadi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The HOXA genes cluster plays a key role in embryologic development. Mutations in HOXA genes have been linked to different human phenotypes, including developmental delay, limb anomalies, and urogenital malformations. The present study reported a clinical and genetic investigation of a female patient with polymalformative syndrome including left arm agenesis, bicornuate uterus and bicuspid aortic valve. Using whole exome sequencing, two heterozygous missense variants were identified. Of these, one was a novel variant in the HOXA13 gene [p.(Tyr290Ser)] and the second a heterozygous variant in the HOXA9 gene [p.(Ala102Pro)]. To the best of our knowledge, this is the first association of HOXA9/HOXA13 point mutations linked to a syndromic case. In conclusion, the present study suggested that the phenotypic spectrum of vertebral anomalies, anal atresia, cardiac defects, tracheo‑esophageal fistula, renal anomalies and limb abnormalities/hand‑foot‑genital syndrome may be attributable to the combination of different HOXA variants, particularly in patients with a severe clinical presentation. The current report contributed as well to the molecular understanding of HOXA genes‑related phenotypes via the identification of novel variant and genes associations.

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1	Krumlauf R: Hox genes, clusters and collinearity. Int J Dev Biol. 62:659–663. 2018. View Article : Google Scholar : PubMed/NCBI
2	Mallo M and Alonso CR: The regulation of Hox gene expression during animal development. Development. 140:3951–3963. 2013. View Article : Google Scholar : PubMed/NCBI
3	Favier B and Dollé P: Developmental functions of mammalian Hox genes. Mol Hum Reprod. 3:115–131. 1997. View Article : Google Scholar : PubMed/NCBI
4	Quinonez SC and Innis JW: Human HOX gene disorders. Mol Genet Metab. 111:4–15. 2014. View Article : Google Scholar : PubMed/NCBI
5	Du H and Taylor HS: The role of Hox genes in female reproductive tract development, adult function, and fertility. Cold Spring Harb Perspect Med. 6:a0230022015. View Article : Google Scholar : PubMed/NCBI
6	Cao L, Chen C, Leng Y, Yan L, Wang S, Zhang X and Luo Y: A missense mutation of HOXA13 underlies hand-foot-genital syndrome in a Chinese family. J Genet. 96:647–652. 2017. View Article : Google Scholar : PubMed/NCBI
7	Jorgensen EM, Ruman JI, Doherty L and Taylor HS: A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of Müllerian fusion anomalies. Fertil Steril. 94:1235–1238. 2010. View Article : Google Scholar : PubMed/NCBI
8	Roux M, Bouchard M and Kmita M: Multifaceted Hoxa13 function in urogenital development underlies the hand-foot-genital syndrome. Hum Mol Genet. 28:1671–1681. 2019. View Article : Google Scholar : PubMed/NCBI
9	Mortlock DP and Innis JW: Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 15:179–180. 1997. View Article : Google Scholar : PubMed/NCBI
10	Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, Innis JW, Holmes LB, Donnenfeld AE, Feingold M, et al: Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet. 67:197–202. 2000. View Article : Google Scholar : PubMed/NCBI
11	Imagawa E, Kayserili H, Nishimura G, Nakashima M, Tsurusaki Y, Saitsu H, Ikegawa S, Matsumoto N and Miyake N: Severe manifestations of hand-foot-genital syndrome associated with a novel HOXA13 mutation. Am J Med Genet A. 164A:2398–2402. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wallis M, Tsurusaki Y, Burgess T, Borzi P, Matsumoto N, Miyake N, True D and Patel C: Dual genetic diagnoses: Atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1. Am J Med Genet A. 170:717–724. 2016. View Article : Google Scholar : PubMed/NCBI
13	Guttmacher AE: Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias. Am J Med Genet. 46:219–222. 1993. View Article : Google Scholar : PubMed/NCBI
14	Innis JW, Goodman FR, Bacchelli C, Williams TM, Mortlock DP, Sateesh P, Scambler PJ, McKinnon W and Guttmacher AE: A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome. Hum Mutat. 19:573–574. 2002. View Article : Google Scholar : PubMed/NCBI
15	Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, Tibboel D, Reutter H and Giampietro PF: Clinical geneticists' views of VACTERL/VATER association. Am J Med Genet A. 158A:3087–3100. 2012. View Article : Google Scholar : PubMed/NCBI
16	van de Putte R, Dworschak GC, Brosens E, Reutter HM, Marcelis CLM, Acuna-Hidalgo R, Kurtas NE, Steehouwer M, Dunwoodie SL, Schmiedeke E, et al: A genetics-first approach revealed monogenic disorders in patients with ARM and VACTERL anomalies. Front Pediatr. 8:3102020. View Article : Google Scholar : PubMed/NCBI
17	Solomon BD, Baker LA, Bear KA, Cunningham BK, Giampietro PF, Hadigan C, Hadley DW, Harrison S, Levitt MA, Niforatos N, et al: An approach to the identification of anomalies and etiologies in neonates with identified or suspected VACTERL (vertebral defects, anal atresia, tracheo-esophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies) association. J Pediatr. 164:451–457.e1. 2014. View Article : Google Scholar : PubMed/NCBI
18	Garcia-Barceló MM, Wong KK, Lui VC, Yuan ZW, So MT, Ngan ES, Miao XP, Chung PH, Khong PL and Tam PK: Identification of a HOXD13 mutation in a VACTERL patient. Am J Med Genet A. 146A:3181–3185. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kang J, Mao M, Zhang Y, Ai FF and Zhu L: Congenital anal atresia with rectovestibular fistula, scoliosis, unilateral renal agenesis, and finger defect (VACTERL association) in a patient with partial bicornuate uterus and distal vaginal atresia: A case report. Medicine (Baltimore). 97:e128222018. View Article : Google Scholar : PubMed/NCBI
20	Komura M, Kanamori Y, Sugiyama M, Tomonaga T, Suzuki K, Hashizume K and Goishi K: A female infant who had both complete VACTERL association and MURCS association: Report of a case. Surg Today. 37:878–880. 2007. View Article : Google Scholar : PubMed/NCBI
21	Obeidat RA, Aleshawi AJ, Tashtush NA and Alsarawi H: Unicornuate uterus with a rudimentary non-communicating cavitary horn in association with VACTERL association: Case report. BMC Womens Health. 19:712019. View Article : Google Scholar : PubMed/NCBI
22	Balusamy SL, Kumar D and Subrahmanian SR: MURCS and VACTERL association in a 27 year old female. J Obstet Gynaecol. 29:762–763. 2009. View Article : Google Scholar : PubMed/NCBI
23	Stephenson JD, Laskowski RA, Nightingale A, Hurles ME and Thornton JM: VarMap: A web tool for mapping genomic coordinates to protein sequence and structure and retrieving protein structural annotations. Bioinformatics. 35:4854–4856. 2019.Available from:. https://academic.oup.com/bioinformatics/article/35/22/4854/5514476 View Article : Google Scholar : PubMed/NCBI
24	Goodman FR and Scambler PJ: Human HOX gene mutations. Clin Genet. 59:1–11. 2001. View Article : Google Scholar : PubMed/NCBI
25	Taylor HS: The role of HOX genes in the development and function of the female reproductive tract. Semin Reprod Med. 18:81–89. 2000. View Article : Google Scholar : PubMed/NCBI
26	He B, Ni ZL, Kong SB, Lu JH and Wang HB: Homeobox genes for embryo implantation: From mouse to human. Animal Model Exp Med. 1:14–22. 2018. View Article : Google Scholar : PubMed/NCBI
27	Sitwala KV, Dandekar MN and Hess JL: HOX proteins and leukemia. Int J Clin Exp Pathol. 1:461–474. 2008.PubMed/NCBI
28	Aryal S, Zhang Y, Wren S, Li C and Lu R: Molecular regulators of HOXA9 in acute myeloid leukemia. FEBS J. Nov 7–2021.(Epub ahead of print). PubMed/NCBI
29	Pérez-Cabrera A, Kofman-Alfaro S and Zenteno JC: Mutational analysis of HOXD13 and HOXA13 genes in the triphalangeal thumb-brachyectrodactyly syndrome. J Orthop Res. 20:899–901. 2002. View Article : Google Scholar : PubMed/NCBI
30	Stern AM, Gall JC Jr, Perry BL, Stimson CW, Weitkamp LR and Poznanski AK: The hand-food-uterus syndrome: A new hereditary disorder characterized by hand and foot dysplasia, dermatoglyphic abnormalities, and partial duplication of the female genital tract. J Pediatr. 77:109–116. 1970. View Article : Google Scholar : PubMed/NCBI
31	Frisén L, Lagerstedt K, Tapper-Persson M, Kockum I and Nordenskjöld A: A novel duplication in the HOXA13 gene in a family with atypical hand-foot-genital syndrome. J Med Genet. 40:e492003. View Article : Google Scholar : PubMed/NCBI
32	Innis JW, Mortlock D, Chen Z, Ludwig M, Williams ME, Williams TM, Doyle CD, Shao Z, Glynn M, Mikulic D, et al: Polyalanine expansion in HOXA13: Three new affected families and the molecular consequences in a mouse model. Hum Mol Genet. 13:2841–2851. 2004. View Article : Google Scholar : PubMed/NCBI
33	Thompson AA and Nguyen LT: Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 26:397–398. 2000. View Article : Google Scholar : PubMed/NCBI