Consanguinity and its relevance for the incidence of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS): systematic review

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

“…Though this ascertainment issue is inherent to our study design, it primarily led to the inclusion of a number of cases that did not meet strict criteria for MMIHS or CIPO and who often ultimately had nondiagnostic molecular studies. This bias would, therefore, lead us to underestimate the impact of ACTG2 in MMIHS/CIPO, which actually strengthens our conclusion that ACTG2 , and not recessive loci as others have proposed (Nakamura et al, ), is the primary genetic factor in MMIHS. Indeed, in a highly clinically selected cohort, it is possible that the rate of ACTG2 ‐positive cases could be even higher than 60%.…”

“…The inheritance pattern of MMIHS varies depending on genetic cause with ACTG2 cases presenting as sporadic or a dominant trait (Wangler et al, ), but familial cases with consanguinity point to the recessive loci (Nakamura, O'Donnell, & Puri, ). In the present cohort, five families exhibited an apparently recessive pattern of inheritance where affected siblings had apparently unaffected parents (Fam10, Fam19, Fam33, Fam36, and Fam44); consanguinity was reported in three of these cases (3/53, 5.6%).…”

“…Since the earliest efforts to apply genomics to MMIHS, consanguinity has been observed in some cases. Despite, the data on ACTG2 and de novo events, it was recently suggested that based on the rates of consanguinity that MMIHS should be considered primarily an autosomal recessive disorder (Nakamura et al, ). We, therefore, explored the apparent recessive cases in our cohort.…”

“…One of the key insights of our study is the central role that ACTG2 mutations and particularly arginine missense substitutions play in this spectrum of disease. Previously, evidence from some cohorts had also pointed to this predominant role for this locus in MMIHS (Ravenscroft et al, ), however, others have suggested that MMIHS is mostly an autosomal recessive disorder and that consanguinity is a major genetic risk factor (Nakamura et al, ) and indeed a number of recessive loci have been described (Gauthier et al, ; Halim, Brosens, et al, ; Halim, Wilson, et al, ; Moreno et al, ). Our cohort included four families with affected siblings and three with consanguinity, but interestingly, one of these cases was ultimately explained by the dominant inheritance of an ACTG2 variant with incomplete penetrance in the mother.…”

“…The inheritance pattern of MMIHS varies depending on genetic cause with ACTG2 cases presenting as sporadic or a dominant trait (Wangler et al, 2014), but familial cases with consanguinity point to the recessive loci (Nakamura, O'Donnell, & Puri, 2019).…”