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

ABSTRACT: OBJECTIVES:The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin ?-2 (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 chronic intestinal pseudo-obstruction. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands and 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 out of 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. CONCLUSIONS:Pooled gene sequencing results from 1 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.

SUBMITTER: Milunsky A

PROVIDER: S-EPMC5610062 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Milunsky Aubrey A Baldwin Clinton C Zhang Xiaoying X Primack Daniel D Curnow Adrian A Milunsky Jeff J

Journal of pediatric gastroenterology and nutrition 20171001 4

<h4>Objectives</h4>The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin γ-2 (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.<h4>Methods</h4>Whole exome sequencing was performed in 4 probands with chronic intestinal pseudo-obstructi ...[more]

PMID: 28422808

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Project description:BACKGROUND: Chronic idiopathic intestinal pseudo-obstruction, a syndrome of ineffectual motility due to a primary disorder of enteric nerve or muscle, is rare. AIMS: To determine the clinical spectrum, underlying pathologies, response to treatments, and prognosis in a consecutive unselected group of patients. METHODS: Cross sectional study of all patients with clinical and radiological features of intestinal obstruction in the absence of organic obstruction, associated with dilated small intestine (with or without dilated large intestine), being actively managed in one tertiary referral centre at one time. RESULTS: Twenty patients (11 men and nine women, median age 43 years, range 22-67) fulfilled the diagnostic criteria. Median age at onset of symptoms was 17 years (range two weeks to 59 years). Two patients had an autosomally dominant inherited visceral myopathy. Major presenting symptoms were pain (80%), vomiting (75%), constipation (40%), and diarrhoea (20%). Eighteen patients required abdominal surgery, and a further patient had a full thickness rectal biopsy. The mean time interval from symptom onset to first operation was 5.8 years. Histology showed visceral myopathy in 13, visceral neuropathy in three, and was indeterminate in three. In the one other patient small bowel motility studies were suggestive of neuropathy. Two patients died within two years of symptom onset, one from generalised thrombosis and the other from an inflammatory myopathy. Of the remaining 18 patients, eight were nutritionally independent of supplements, two had gastrostomy or jejunostomy feeds, and eight were receiving home parenteral nutrition. Five patients were opiate dependent, only one patient had benefited from prokinetic drug therapy, and five patients required formal psychological intervention and support. CONCLUSIONS: In a referral setting visceral myopathy is the most common diagnosis in this heterogeneous syndrome, the course of the illness is usually prolonged, and prokinetic drug therapies are not usually helpful. Ongoing management problems include pain relief and nutritional support.

Dataset Information

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

Publications

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

Similar Datasets

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