Abstract

Research Article

Partial SHOX duplications associated with various cases of congenital uterovaginal aplasia (MRKH syndrome): A tangible evidence but a puzzling mechanism

Daniel Guerrier* and Karine Morcel

Published: 24 March, 2021 | Volume 4 - Issue 1 | Pages: 001-008

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is the most severe form of congenital malformation of the inner female reproductive tract. It is diagnosed as such when the uterus, the upper vagina and optionally the Fallopian tubes are absent. It accounts for approximately 1 in 5000 live-born females and has been classified in two subtypes: type 1 in the presence of isolated uterovaginal aplasia and type 2 when associated in various combinations with extragenital malformations of the kidneys, skeleton, heart and auditory system. Most cases of MRKH syndrome are sporadic, although a significant number of many familial cases have been reported to date. Despite numerous studies, the genetics of the syndrome remains largely unknown and appears to be heterogeneous: chromosomal abnormalities and some candidate gene variants appear to be associated with a few cases; others have been suggested but not yet confirmed. To date, mainly the GREB1L gene appears to be a serious candidate. Among the remaining hypotheses, the controversial contribution of partial duplications of the SHOX gene is still puzzling, as the deficiency of this gene is a major cause of skeletal adysplasia syndromes. We have attempted to resolve this controversy in a study of 60 MRKH cases. Our results tend to show that SHOX duplications can be the origin of a genetic mechanism responsible for MRKH syndrome.

Read Full Article HTML DOI: 10.29328/journal.jgmgt.1001006 Cite this Article Read Full Article PDF

Keywords:

CNV; Congenital uterovaginal aplasia; Duplication; MRKH syndrome; SHOX

References

  1. Morcel K, Camborieux L, Guerrier D. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Orphanet J Rare Dis. 2007; 14: 13. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-13
  2. Jacquinet A, Millar D, Lehman A. Etiologies of uterine malformations. Am J Med Genet A. 2016; 170: 2141-2172. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.37775
  3. Herlin M, Bjørn AM, Rasmussen M, et al. Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study. Hum Reprod. 2016; 31: 2384-2390. https://academic.oup.com/humrep/article/31/10/2384/2198191
  4. Acién P, Acién M, Sánchez-Ferrer M. Complex malformations of the female genital tract. New types and revision of classification. Hum Reprod. 2004; 19: 2377-2384. https://academic.oup.com/humrep/article/19/10/2377/589016
  5. Oppelt P, Renner SP, Brucker S, et al. The VCUAM (Vagina Cervix Uterus Adnex-associated Malformation) classification: a new classification for genital malformations. Fertil Steril. 2005; 84: 1493-1467. https://www.fertstert.org/article/S0015-0282(05)02786-X/fulltext
  6. Acién P, Acién MI. The history of female genital tract malformation classifications and proposal of an updated system. Hum Reprod Update. 2011; 17: 693-705. https://academic.oup.com/humupd/article/17/5/693/759275
  7. Grimbizis GF, Gordts S, Di Spiezio Sardo A, et al. The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies. Hum Reprod. 2013; 28: 2032-2044. https://academic.oup.com/humrep/article/28/8/2032/658933
  8. Biason-Lauber A, Konrad D. WNT4 and sex development. Sex Dev. 2008; 2: 210-218. https://www.karger.com/Article/Abstract/152037
  9. Fontana L, Gentilin B, Fedele L, et al. Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Clin Genet. 2017; 91: 233-246. https://onlinelibrary.wiley.com/doi/full/10.1111/cge.12883
  10. Deng S, He Y, Chen N, et al. Spectrum of Type I and Type II Syndromes and Associated Malformations in Chinese Patients with Mayer-Rokitansky-Küster-Hauser Syndrome: A Retrospective Analysis of 274 Cases. J Pediatr Adolesc Gynecol. 2019; 32: 284-287. https://www.jpagonline.org/article/S1083-3188(18)30260-2/fulltext
  11. Herlin MK, Petersen MB, Brännström M. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update. Orphanet J Rare Dis. 2020; 15: 214. https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01491-9
  12. Petrozza JC. Mayer-Rokitansky-Küster-Hauser syndrome and associated malformations: are they as common as we think? Fertil Steril. 2016; 106: 1047-1048. https://www.fertstert.org/article/S0015-0282(16)61388-2/fulltext
  13. Griffin JE, Edwards C, Madden JD, et al. Congenital absence of the vagina. The Mayer-Rokitansky-Kuster-Hauser syndrome. Ann Intern Med. 1976; 85: 224-236. https://www.acpjournals.org/doi/10.7326/0003-4819-85-2-224
  14. Opitz JM. Vaginal atresia (von Mayer-Rokitansky-Küster or MRK anomaly) in hereditary renal adysplasia (HRA). Am J Med Genet. 1987; 26: 873-876. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.1320260414
  15. Guerrier D, Mouchel T, Pasquier L, et al. The Mayer-Rokitansky-Küster-Hauser syndrome (congenital absence of uterus and vagina)--phenotypic manifestations and genetic approaches. J Negat Results Biomed. 2006; 5: 1. https://jnrbm.biomedcentral.com/articles/10.1186/1477-5751-5-1
  16. Schouten JP, McElgunn CJ, Waaijer R, et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002; 30: e57. https://academic.oup.com/nar/article/30/12/e57/2380384
  17. Bernardini L, Gimelli S, Gervasini C, et al. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports. Orphanet J Rare Dis. 2009; 4: 25. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-25
  18. Nik-Zainal S, Strick R, Storer M, et al. High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia. J Med Genet. 2011; 48: 197-204. https://jmg.bmj.com/content/48/3/197
  19. Ledig S, Schippert C, Strick R, et al. Recurrent aberrations identified by array-CGH in patients with Mayer-Rokitansky-Küster-Hauser syndrome. Fertil Steril. 2011; 95: 1589-1594. https://www.fertstert.org/article/S0015-0282(10)02168-0/fulltext
  20. Xia M, Zhao H, Qin Y, et al. LHX1 mutation screening in 96 patients with müllerian duct abnormalities. Fertil Steril. 2012; 97: 682-685. https://www.fertstert.org/article/S0015-0282(11)02857-3/fulltext
  21. Ledig S, Brucker S, Barresi G, et al. Frame shift mutation of LHX1 is associated with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Hum Reprod. 2012; 27: 2872-2875. https://academic.oup.com/humrep/article/27/9/2872/625703
  22. Sandbacka M, Laivuori H, Freitas E, et al. TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia. Orphanet J Rare Dis. 2013; 8: 125. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-125
  23. Williams LS, Demir Eksi D, Shen Y, et al. Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families. Fertil Steril. 2017; 108: 145-151. https://www.fertstert.org/article/S0015-0282(17)30398-9/fulltext
  24. Tewes A-C, Rall KK, Römer T, et al. Variations in RBM8A and TBX6 are associated with disorders of the müllerian ducts. Fertil Steril. 2015; 103: 1313-1318. https://www.fertstert.org/article/S0015-0282(15)00136-3/fulltext
  25. Pan HX, Luo GN, Wan SQ, et al. Detection of de novo genetic variants in Mayer-Rokitansky-Küster-Hauser syndrome by whole genome sequencing. Eur J Obstet Gynecol Reprod Biol X. 2019; 4: 100089. https://www.sciencedirect.com/science/article/pii/S259016131930122X?via%3Dihub
  26. Herlin MK, Le VQ, Allan T Højland AT, Ernst A, Okkels H, et al. Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A case report. Hum Reprod. 2019; 34: 1838-1846. PubMed: https://pubmed.ncbi.nlm.nih.gov/31424080/
  27. Jacquinet A, Boujemla B, Fasquelle C, et al. GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer-Rokitansky-Kuster-Hauser syndrome. Clin Genet. 2020; 98: 126-137. https://onlinelibrary.wiley.com/doi/abs/10.1111/cge.13769
  28. Brophy PD, Rasmussen M, Parida M, et al. A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans. Genetics. 2017; 207: 215-228. https://academic.oup.com/genetics/article/207/1/215/5930718
  29. Nakajima T, Sato T, Iguchi T, et al. Retinoic acid signaling determines the fate of the uterus from the mouse Müllerian duct. Reprod Toxicol. 2019; 86: 56-61. https://www.sciencedirect.com/science/article/pii/S0890623818306105?via%3Dihub
  30. Gervasini C, Grati R, Lalatta F, et al. SHOX duplications found in some cases with type I Mayer-Rokitansky-Kuster-Hauser syndrome. Genet Med. 2010; 12: 634-640. https://www.nature.com/articles/gim2010106
  31. Sandbacka M, Halttunen M, Jokimaa V, et al. Evaluation of SHOX copy number variations in patients with Müllerian aplasia. Orphanet J Rare Dis. 2011; 6: 53. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-53
  32. Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr. 2011; 75: 81-89. https://www.karger.com/Article/FullText/324105
  33. Bunyan DJ, Baker KR, Harvey JF, et al. Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5 kb deletion 160 kb downstream with a variable phenotypic effect. Am J Med Genet A. 2013; 161A: 1329-1338. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.35919
  34. Marchini A, Ogata T, Rappold GA. A Track Record on SHOX: From Basic Research to Complex Models and Therapy. Endocr Rev. 2016; 37: 417-448. https://academic.oup.com/edrv/article/37/4/417/2567101
  35. Dehainault C, Laugé A, Caux-Moncoutier V, et al. Multiplex PCR/liquid chromatography assay for detection of gene rearrangements: application to RB1 gene. Nucleic Acids Res. 2004; 32: e139. https://academic.oup.com/nar/article/32/18/e139/998831
  36. Bendavid C, Pasquier L, Watrin T, et al. Phenotypic variability of a 4q34-->qter inherited deletion: MRKH syndrome in the daughter, cardiac defect and Fallopian tube cancer in the mother. Eur J Med Genet. 2007; 50: 66-72. https://www.sciencedirect.com/science/article/pii/S1769721206000991?via%3Dihub
  37. Morcel K, Watrin T, Pasquier L, et al. Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci. Orphanet J Rare Dis. 2011; 6: 9. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-9
  38. Pontecorvi P, Bernardini L, Capalbo A, et al. Protein-protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer-Rokitansky-Küster-Hauser syndrome. Sci Rep. 2021; 11: 448. https://www.nature.com/articles/s41598-020-79827-5
  39. Chen J, Wildhardt G, Zhong Z, et al. Enhancer deletions of the SHOX gene as a frequent cause of short stature: the essential role of a 250 kb downstream regulatory domain. J Med Genet. 2009; 46: 834-839. https://jmg.bmj.com/content/46/12/834
  40. Benito-Sanz S, Barroso E, Heine-Suner D, et al. Clinical and molecular evaluation of SHOX/PAR1 duplications in Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS). J Clin Endocrinol Metab. 2011; 96: E404-412. https://doi.org/10.1210/jc.2010-1689
  41. Rao E, Weiss B, Fukami M, et al. FISH-deletion mapping defines a 270-kb short stature critical interval in the pseudoautosomal region PAR1 on human sex chromosomes. Hum Genet. 1997; 100: 236-239. https://link.springer.com/article/10.1007/s004390050497
  42. Ogata T, Matsuo N, Nishimura G. SHOX haploinsufficiency and overdosage: impact of gonadal function status. J Med Genet. 2001; 38: 1-6. https://jmg.bmj.com/content/38/1/1
  43. Benito-Sanz S, Thomas NS, Huber C, et al. A novel class of Pseudoautosomal region 1 deletions downstream of SHOX is associated with Leri-Weill dyschondrosteosis. Am J Hum Genet. 2005; 77: 533-544. https://www.cell.com/ajhg/fulltext/S0002-9297(07)61002-7
  44. Benito-Sanz S, Belinchon-Martínez A, et al. Identification of 15 novel partial SHOX deletions and 13 partial duplications, and a review of the literature reveals intron 3 to be a hotspot region. J Hum Genet. 2017; 62: 229-234. https://www.nature.com/articles/jhg2016113
  45. Tiecke E, Bangs F, Blaschke R, et al. Expression of the short stature homeobox gene SHOX is restricted by proximal and distal signals in chick limb buds and affects the length of skeletal elements. Dev Biol. 2006; 298: 585-596. https://www.sciencedirect.com/science/article/pii/S0012160606009900?via%3Dihub
  46. Thomas NS, Harvey JF, Bunyan DJ, et al. Clinical and molecular characterization of duplications encompassing the human SHOX gene reveal a variable effect on stature. Am J Med Genet A. 2009; 149A: 1407-1414. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.32914
  47. Upners EN, Jensen RB, Rajpert-De Meyts E, et al. Short stature homeobox-containing gene duplications in 3.7% of girls with tall stature and normal karyotypes. Acta Paediatr. 2017; 106: 1651-1657. https://onlinelibrary.wiley.com/doi/abs/10.1111/apa.13969
  48. Ramirez JM, Rodríguez FA, Echeverría MI, et al. SHOX Duplication and Tall Stature in a Patient with Xq Deletion and Vascular Disease. Case Rep Genet. 2019; 2019: 2691820. https://www.hindawi.com/journals/crig/2019/2691820/
  49. Fukami M, Naiki Y, Muroya K, et al. Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature. J Hum Genet. 2015; 60: 553-556. https://www.nature.com/articles/jhg201553
  50. Hirschfeldova K, Solc R. Comparison of SHOX and associated elements duplications distribution between patients (Lėri-Weill dyschondrosteosis/idiopathic short stature) and population sample. Gene. 2017; 627: 164-168. https://www.sciencedirect.com/science/article/pii/S0378111917304845?via%3Dihub
  51. Tropeano M, Howley D, Gazzellone MJ, et al. Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions. J Med Genet. 2016; 53: 536-547. https://jmg.bmj.com/content/53/8/536
  52. Rall K, Eisenbeis S, Henninger V, et al. Typical and Atypical Associated Findings in a Group of 346 Patients with Mayer-Rokitansky-Kuester-Hauser Syndrome. J Pediatr Adolesc Gynecol. 2015; 28: 362-368. https://www.jpagonline.org/article/S1083-3188(14)00369-6/fulltext
  53. Kapczuk K, Iwaniec K, Friebe Z, et al. Congenital malformations and other comorbidities in 125 women with Mayer-Rokitansky-Küster-Hauser syndrome. Eur J Obstet Gynecol Reprod Biol. 2016; 207: 45-49. https://www.ejog.org/article/S0301-2115(16)30962-9/fulltext
  54. Rappold G, Blum WF, Shavrikova EP, et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet. 2007; 44: 306-313. https://jmg.bmj.com/content/44/5/306
  55. Turner DJ, Miretti M, Rajan D, et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet. 2008; 40: 90-95. https://www.nature.com/articles/ng.2007.40
  56. May CA, Shone AC, Kalaydjieva L, et al. Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. Nat Genet. 2002; 31: 272-275. https://www.nature.com/articles/ng918z
  57. Lien S, Szyda J, Schechinger B, et al. Evidence for heterogeneity in recombination in the human pseudoautosomal region: high resolution analysis by sperm typing and radiation-hybrid mapping. Am J Hum Genet. 2000; 66: 557-566. https://www.cell.com/ajhg/fulltext/S0002-9297(07)63430-2
  58. Hastings PJ, Lupski JR, Rosenberg SM, et al. Mechanisms of change in gene copy number. Nat Rev Genet. 2009; 10: 551-564. https://www.nature.com/articles/nrg2593
  59. Schneider KU, Sabherwal N, Jantz K, et al. Identification of a major recombination hotspot in patients with short stature and SHOX deficiency. Am J Hum Genet. 2005; 77: 89-96. https://www.cell.com/ajhg/fulltext/S0002-9297(07)60904-5
  60. Newman S, Hermetz KE, Weckselblatt B, et al. Next-generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. Am J Hum Genet. 2015; 96: 208-220. https://www.cell.com/ajhg/fulltext/S0002-9297(14)00523-0

Figures:

Figure 1

Figure 1

Figure 1

Figure 2

Figure 1

Figure 3

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More