Abstract
Chronic intestinal pseudo-obstruction (CIPO) syndromes are heterogeneous gastrointestinal disorders, caused by either neuropathy or myopathy, resulting in compromised peristalsis and intestinal obstruction. CIPO can have a profound impact on quality of life, leading the most severely affected individuals to life-long parenteral nutrition and urinary catheterization. To search for disease causing gene(s), we performed the whole exome sequencing (WES) in both eight sporadic and two familial cases, followed by targeted sequencing in additional CIPO patients. After identifying a heterozygous missense variant in the ACTG2 gene in one of 10 patients undergone WES, targeted Sanger sequencing of this gene allowed to detect heterozygous missense variants in 9 of 23 further patients with either megacystis-microcolon-intestinal hypoperistalsis syndrome or intestinal pseudo-obstruction. Variants thus identified, one of which still unreported, affect highly conserved regions of the ACTG2 gene that encodes a protein crucial for correct enteric muscle contraction. These findings provided evidence for a correlation between the clinical phenotype and genotype at the ACTG2 locus, a first step to improve the diagnosis and prognosis of these severe conditions.
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Acknowledgements
We thank Giuseppe Santamaria for his technical support, and all the patients and families for participating in this study. We would also like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. This work was supported by the Italian Ministry of Health through, both grant RF-2010–2314356, ‘Cinque per mille’ and Ricerca Corrente to the Gaslini Institute; a research grant from the Shenzhen Municipal Government of China (NO.CXZZ20130517144604091) and the Institutional Development Funds to Dr Hakon Hakonarson (Center for Applied Genomics at the Children’s Hospital of Philadelphia).
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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 24, 1211–1215 (2016). https://doi.org/10.1038/ejhg.2015.275
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DOI: https://doi.org/10.1038/ejhg.2015.275
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