Somatic mutation, a cause of biliary atresia: A hypothesis. (May 2017)

• Record Type: Journal Article
• Authors: Fabre, Alexandre; Roman, Céline; Roquelaure, Bertrand
• Is Part Of: Medical hypotheses. Volume 102(2017)
• Page Start: 91
• Page End: 93
• Publication Date: 2017-05
• Subjects: Biliary atresia -- Somatic mutation -- Twin studies; Medicine -- Periodicals; Medicine -- Periodicals; Médecine -- Périodiques; Medicine; Periodicals; 610
• DOI: 10.1016/j.mehy.2017.03.015
• Languages: English
• ISSNs: 0306-9877

Abstract

Abstract: Despite many years of research, the causes of biliary atresia still remain elusive. Infection, immune disorder, toxins or maternal microchimerism have been cited as potential triggers of biliary atresia. This is a rare disease with a stable incidence over the years although with sizeable ethnic variations. This stability suggests that environmental factors have in fact only a slight influence. During the search for etiologies, twin studies have often helped disentangle the genetic from the environmental. For this condition, twin studies have mainly demonstrated a lack of concordance between twins (either monozygotic or dizygotic), ruling out Mendelian, infectious or toxic causes. Indeed, for toxic or infectious embryopathy, the concordance for twins (especially monozygotic) is about 80%. Paradoxically, these data suggest that biliary atresia has neither a genetic nor an environmental cause. One way of severing the Gordian knot is to hypothesize a role for post zygotic somatic mutation, leading to genetic mosaicism (as a cause of biliary atresia). In recent years, post zygotic mutation has been identified as a cause of non-cancerous disease ranging from dysmorphic syndrome to specific organ abnormalities. A potential model for this condition could be post zygotic mutation or copy number variations in genes or regulatory regions, triggering the cascade of events leading to inflammatory and obliterative cholangiopathy. These events could be enhanced by genetic susceptibility explaining the ethnic variations. In these models, the rate of mosaicism in different parts of the liver could explain the success rate of the Kasai procedure. This hypothesis can be tested: as most children with biliary atresia are eligible for the Kasai procedure, genetic material from the liver and ductal plate can be collected easily. If the hypothesis is correct, whole genome sequencing or copy number variation studies at individual cell level should allow to identify the expected low level of genetic mosaicism. Thus, we hypothesize that postzygotic somatic mutation may play a part in the physiopathology of biliary atresia.