J Neurogastroenterol Motil 2022; 28(3): 501-502  https://doi.org/10.5056/jnm22017
Comment to the Description of a Novel Cohesinopathy in Chronic Intestinal Pseudo Obstruction
Elena Bonora,1* Francesca Bianco,1,2 and Roberto De Giorgio3
1Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Italy; 2Department of Veterinary Medical Sciences, University of Bologna, Italy; and 3Department of Translational Medicine, St. Anna Hospital, University of Ferrara, Italy
Published online: July 30, 2022
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

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TO THE EDITOR: We read with great interest the article “A novel cohesinopathy causing chronic intestinal pseudo obstruction in 2 siblings and literature review” by Venkatesh et al1 reporting on a gene mutation in 2 patients with a clinical phenotype of chronic intestinal pseudo-obstruction (CIPO). The topic of the genetic analysis in rare forms of severe gut dysmotility is extremely cogent in the neurogastroenterology area especially because the management of CIPO is still largely ineffective and mainly centered on general measures (hydro-electrolyte balance and adequate caloric support often via parenteral nutrition). Thus, investigating genetic and molecular mechanisms may unveil novel therapeutic approaches for this orphan disorder. In any affected patient, either adult or pediatric, CIPO is characterized by a marked derangement of gut propulsion, mimicking a mechanical sub-occlusion, in the absence of any anatomical cause of obstruction. The severity of the clinical presentation is typically associated with disabling digestive symptoms, which contribute to poor quality of life and increased mortality. In the last years, several genetic causes have been identified in different subsets of CIPO patients. Heterozygous mutations in the ACTG2 gene were found in patients with CIPO characterized by degeneration of enteric smooth muscle, as well as in the “megacystis, microcolon, and intestinal hypoperistalsis” syndrome.2-5 X-linked CIPO has been ascribed to filamin A gene mutations.6,7 TYMP, POLG, and LIG3 genes have been demonstrated in recessive forms of mitochondrial CIPO.8-10 Finally, homozygous mutations in SGOL1 and RAD21 genes, encoding for members of the cohesin complex, have been identified in another subset of CIPO in association with additional clinical manifestations, ie, chronic atrial and intestinal dysrhythmia (CAID),11 or cardiac defect and long Barrett esophagus in Mungan’s syndrome,12,13 respectively. Both SGOL1 and RAD21 mutations are known to be causative of these 2 forms of “cohesinopathy” underlying CIPO.

In this context, Venkatesh et al1 identified a homozygous variant in SGOL1 in 2 siblings using next-generation sequencing analysis. The mutation was correctly interpreted to be causative, although the authors did not inform whether a target gene panel analysis, whole exome or whole genome sequencing was performed. These methodological approaches are of critical importance to exclude the presence of other putative variants of interest. Moreover, the identified variant (p.Lys23Glu) is exactly the same of that reported by Chetaille et al11 who showed a causative homozygous variant in several Canadian pedigrees with patients affected by CIPO and atrial dysrhythmia (hence CAID, as previously mentioned). We address this in order to avoid possible misinterpretation by the reader. It would be always important to report the genomic coordinates and the dbSNP ID of a variant, as in the current case (rs199815268). This finding facilitates comparison between studies and can help identifying clinical convergence and/or differences among CIPO patients. Furthermore, the segregation of the selected variants should be pursued when possible in order to confirm that the pattern(s) of inheritance is/are correct. Since there was no report of consanguinity in the family reported by Venkatesh et al,1 it would be very important to prove that both parents were heterozygous carriers, maybe again due to a founder effect in the corresponding geographical area, as observed in the original paper by Chetaille et al11 in the described Canadian families.

In conclusion, we commend Venkatesh et al1 for their effort aimed at identifying CIPO-causative variants, which is a pivotal approach to better understand the molecular defects underlying this difficult and highly challenging condition. However, data regarding mutations of any detected variants should be carefully detailed to provide a clear-cut understanding for all readers.

Financial support

This work was supported by Telethon Grant GGP15171 to Elena Bonora and Roberto De Giorgio. Roberto De Giorgio is the recipient of grants from University of Ferrara (FAR funds). Francesca Bianco is supported by a post-doctoral fellowship from the University of Bologna.

Conflicts of interest

None.

Author contributions

Elena Bonora, Francesca Bianco, and Roberto De Giorgio designed and wrote the manuscript

References
  1. Venkatesh V, Aneja A, Seetharaman K, Anushree N, Rana SS, Lal SB. A novel cohesinopathycausing chronic intestinal pseudo obstruction in 2 siblings and literature review. J Neurogastroenterol Motil 2021;27:436-437.
    Pubmed KoreaMed CrossRef
  2. Lehtonen HJ, Sipponen T, Tojkander S, et al. Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy. Gastroenterology 2012;143:1482-1491, e3.
    Pubmed CrossRef
  3. Knowles CH, Lindberg G, Panza E, De Giorgio R. New perspectives in the diagnosis and management of enteric neuropathies. Nat Rev Gastroenterol Hepatol 2013;10:206-218.
    Pubmed CrossRef
  4. Wangler MF, Gonzaga-Jauregui C, Gambin T, et al. Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. PLoS Genet 2014;10:e1004258.
    Pubmed KoreaMed CrossRef
  5. Matera I, Rusmini M, Guo Y, et al. Variants of the ACTG2 gene correlate with degree of severity and presence of megacystis in chronic intestinal pseudo-obstruction. Eur J Hum Genet 2016;24:1211-1215.
    Pubmed KoreaMed CrossRef
  6. Gargiulo A, Auricchio R, Barone MV, et al. Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. Am J Hum Genet 2007;80:751-758.
    Pubmed KoreaMed CrossRef
  7. Clayton-Smith J, Walters S, Hobson E, et al. Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. Eur J Hum Genet. 2009;17:434-443.
    Pubmed KoreaMed CrossRef
  8. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999;283:689-692.
    Pubmed CrossRef
  9. Van Goethem G, Schwartz M, Löfgren A, Dermaut B, Van Broeckhoven C, Vissing J. Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 2003;11:547-549.
    Pubmed CrossRef
  10. Bonora E, Chakrabarty S, Kellaris G, et al. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy. Brain 2021;144:1451-1466.
    Pubmed CrossRef
  11. Chetaille P, Preuss C, Burkhard S, et al. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet 2014;46:1245-1249.
    Pubmed CrossRef
  12. Mungan Z, Akyüz F, Bugra Z, et al. Familial visceral myopathy with pseudo-obstruction, megaduodenum, Barrett's esophagus, and cardiac abnormalities. Am J Gastroenterol 2003;98:2556-2560.
    Pubmed CrossRef
  13. Bonora E, Bianco F, Cordeddu L, et al. Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction. Gastroenterology 2015;148:771-782, e11.
    Pubmed KoreaMed CrossRef


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