Diagnosis of Chronic Intestinal Pseudo‐obstruction and Megacystis by Sequencing the ACTG2 Gene

Abstract

Objectives The diagnosis of chronic intestinal pseudo-obstruction (CIPO) has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the ACTG2 gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously. Methods Whole exome sequencing was performed in 4 probands with CIPO. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands plus our 28 [total 111] and determined how many had pathogenic variants and the precise genotype. Results Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4/28 of our probands and in 45 out of 83 published probands [49/111(44.1%)]. Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident. Conclusion Pooled gene sequencing results from one individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50% risk of recurrence, provides an opportunity for genetic counseling.

Pediatric Intestinal Failure: The Key Outcomes for the First 100 Patients Treated in a National Tertiary Referral Center During 1984–2017

“…However, most tolerated some enteral feeds, reducing the risk for IFALD, and CRBSI rates were low. Specific genotypes for PIMDs are identified increasingly . Although we were able to histologically classify most of our patients with CIPO, only 1 had an established genetic background (ACTG2 mutation) despite meticulous clinical workup.…”

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

“…We and others identified ACTG2 as the first single gene for the disease traits of visceral myopathy (Lehtonen et al, ), and MMIHS/CIPO (Thorson et al, ; Wangler et al, ). Subsequent reports, supported by functional data from mouse models, established the important role of ACTG2 in these disorders (Halim et al, ; Holla, Bock, Busk, & Isfoss, ; Klar et al, ; Lu et al, ; Matera et al, ; Milunsky, Baldwin, et al, ; Milunsky, Lazier, et al, ; Moreno et al, ; Tuzovic et al, ; Whittington, Poole, Dutta, & Munn, ). ACTG2 encodes a muscle actin isoform predominantly expressed in the intestinal smooth muscle (Miwa et al, ; Szucsik & Lessard, ) which, together with myosin, comprises the apparatus responsible for muscle contraction and relaxation.…”

Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing

“…A Japanese study suggests a prevalence estimation of 1.00 and 0.80 cases per 100 000 males and females for those with severe disease . Autosomal dominant mutations in the smooth muscle actin gene, ACTG2 , accounts for 44%‐50% of CIPO patients . ACTG2 encodes the smooth muscle γ‐2, which is predominantly expressed in enteric tissue.…”