Hypomorphic SI genetic variants are associated with childhood chronic loose stools

Bruno P Chumpitazi; Jeffery Lewis; Derick Cooper; Mauro D’Amato; Joel Lim; Sandeep Gupta; Adrian Miranda; Natalie Terry; Devendra Mehta; Ann Scheimann; Molly O’Gorman; Neelesh Tipnis; Yinka Davies; Joel Friedlander; Heather Smith; Jaya Punati; Julie Khlevner; Mala Setty; Carlo Di Lorenzo

doi:10.1371/journal.pone.0231891

. 2020 May 20;15(5):e0231891. doi: 10.1371/journal.pone.0231891

Hypomorphic SI genetic variants are associated with childhood chronic loose stools

Bruno P Chumpitazi ^1,^*, Jeffery Lewis ^2,^#, Derick Cooper ^3,^#, Mauro D’Amato ^4,^#, Joel Lim ^5,^#, Sandeep Gupta ^6,^#, Adrian Miranda ^7,^#, Natalie Terry ^8,^#, Devendra Mehta ^9,^#, Ann Scheimann ^10,^#, Molly O’Gorman ^11,^#, Neelesh Tipnis ^12,^#, Yinka Davies ^13,^#, Joel Friedlander ^14,^#, Heather Smith ^3,^#, Jaya Punati ^15,^#, Julie Khlevner ^16,^#, Mala Setty ^17,^#, Carlo Di Lorenzo ^18,^#

Editor: Adriana Calderaro¹⁹

¹Baylor College of Medicine, Houston, TX, United States of America

²Children’s Center for Digestive Health Care, Atlanta, GA, United States of America

³QOL Medical, LLC, Vero Beach, FL, United States of America

⁴School of Biological Sciences, Monash University, Clayton, VIC, Australia

⁵Children's Mercy Hospital, Kansas City, MO, United States of America

⁶Sacramento Pediatric Gastroenterology, Sacramento, CA, United States of America

⁷Children’s Hospital of Wisconsin, Milwaukee, WI, United States of America

⁸Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America

⁹Arnold Palmer Children's Hospital, Orlando, FL, United States of America

¹⁰Johns Hopkins University, Baltimore, MD, United States of America

¹¹Primary Children's Medical Center, Salt Lake City, UT, United States of America

¹²University of Mississippi Medical Center, Jackson, MS, United States of America

¹³Sacramento Pediatric Gastroenterology, Sacramento, CA, United States of America

¹⁴Children’s Hospital Colorado, Digestive Health Institute, University of Colorado School of Medicine, Aurora, CO, United States of America

¹⁵Children’s Hospital of Los Angeles, Los Angeles, CA, United States of America

¹⁶Columbia University Medical Center, New York, NY, United States of America

¹⁷UCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States of America

¹⁸Department of Pediatrics, The Ohio State University, Columbus, OH, United States of America

¹⁹Universita degli Studi di Parma, ITALY

Competing Interests: Co-authors DC and HS are members of QOL Medical, LLC. QOL Medical LLC markets the product sacrosidase oral solution. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

^✉

* E-mail: chumpita@bcm.edu

Contributed equally.

Roles

Bruno P Chumpitazi: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

Jeffery Lewis: Data curation, Methodology, Writing – review & editing

Derick Cooper: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Supervision, Writing – review & editing

Mauro D’Amato: Data curation, Formal analysis, Methodology, Writing – review & editing

Joel Lim: Data curation, Methodology, Writing – review & editing

Sandeep Gupta: Data curation, Methodology, Writing – review & editing

Adrian Miranda: Data curation, Methodology, Writing – review & editing

Natalie Terry: Data curation, Methodology, Writing – review & editing

Devendra Mehta: Data curation, Methodology, Writing – review & editing

Ann Scheimann: Data curation, Methodology, Writing – review & editing

Molly O’Gorman: Data curation, Methodology, Writing – review & editing

Neelesh Tipnis: Data curation, Methodology, Writing – review & editing

Yinka Davies: Data curation, Methodology, Writing – review & editing

Joel Friedlander: Data curation, Methodology, Writing – review & editing

Heather Smith: Methodology, Writing – review & editing

Jaya Punati: Data curation, Methodology, Writing – review & editing

Julie Khlevner: Data curation, Methodology, Writing – review & editing

Mala Setty: Data curation, Methodology, Writing – review & editing

Carlo Di Lorenzo: Data curation, Methodology, Writing – review & editing

Adriana Calderaro: Editor

PMCID: PMC7239456 PMID: 32433684

Abstract

Objective

The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population.

Methods

A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference.

Results

Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02).

Conclusion

Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.

Introduction

A large number of children around the world experience chronic gastrointestinal (GI) symptoms diagnosed as functional (nonorganic) GI disorders [1]. Functional GI disorders may have several contributing pathophysiologic factors, including carbohydrate malabsorption [2]. The sucrase-isomaltase enzyme, encoded by the SI gene, is a predominant member of the disaccharidases responsible for the digestion of dietary carbohydrates in humans [3]. Hypomorphic SI gene variants reduce enzyme activity, resulting in congenital sucrase-isomaltase deficiency (CSID) and characteristic GI symptoms. To date, 37 SI variants have been identified in diagnosed CSID patients and found to be hypomorphic [4–12]. Patients with CSID experience sucrose malabsorption, leading to colonic osmosis and fermentation, and subsequent osmotic diarrhea and excessive flatulence [4, 13]. Heterozygotes of hypomorphic SI variants may also experience GI symptoms. Small case reports have associated hypomorphic SI heterozygosity with decreased intestinal sucrase enzymatic activity and characteristic GI symptoms [3, 12, 14]. In two recent studies, the prevalence of heterozygous carriers of hypomorphic SI variants was small but significantly greater among adults diagnosed with irritable bowel syndrome (IBS) than in controls, suggestive of an increased IBS susceptibility [15, 16].

A subset of children with functional GI disorders has frequent diarrhea. Currently, the potential contribution of hypomorphic SI variants in these children is unknown. Therefore, we had two primary study objectives. The first study objective was to determine the relative prevalence of hypomorphic SI variants among children with chronic, idiopathic, loose stools versus the general population. The second study objective in children with chronic, idiopathic, loose stools was to determine the potential impact of hypomorphic SI variants on symptom burden.

Methods

Study design and subjects

A prospective, 18-center study conducted in the United States enrolled subjects ≤18 years old who presented at a pediatric gastroenterology center with loose stools at least once per week for a minimum of 4 weeks.

The study objectives were i) to determine the prevalence of hypomorphic SI variants within the study population versus a genetic database for the general population, and ii) to determine the symptom burden among the study subjects with hypomorphic SI variants versus study subjects without hypomorphic SI variants.

Exclusion criteria included: identification of any condition(s) or finding(s) that, in the opinion of the investigator, suggested an organic etiology for the subject’s GI symptoms; abdominal pain primarily related to constipation; suspected GI infectious disease or other infectious diseases; known GI disease (eg, celiac disease); a history of antibiotic therapy or viral gastroenteritis within the previous 2 weeks; known hepatitis B or C infection or chronic liver disease; cancer or systemic infections; severe neurologic impairment (preventing reporting of symptoms); planned or previous abdominal surgery (eg, bowel resection); severe, uncontrolled systemic diseases; or current use of sacrosidase, an enzyme replacement therapy for CSID.

The pediatric gastroenterology centers in this study were comprised of private practices and academic centers. Each investigator was asked to follow his or her standard clinical practice to ensure an organic etiology was not present. Evaluations took place during a clinic visit. All participating centers received approval from their local institutional review boards (IRB). The institutional review boards included: Baylor College of Medicine IRB, Children's Hospital Los Angeles Committee on Clinical Investigators, Nationwide Children's Hospital IRB, Children's Mercy Hospital Pediatric IRB, Johns Hopkins IRB, The Children's Hospital of Philadelphia Research Institute IRB, The Arnold Palmer Medical Center IRB, The Duke University Health System IRB, Massachusetts General Hospital IRB, Children's Hospital of Wisconsin IRB, Colorado Multiple IRB, The Indiana University IRB, Children's Healthcare of Atlanta IRB, The University of Utah IRB, Children's Hospital & Research Center Oakland IRB, University of Mississippi Medical Center IRB, Columbia University Medical Center IRB, and Sutter Health IRB. All subjects provided assent with a legal guardian providing written informed consent. The study was conducted from May 2013 to July 2015. All authors had access to the study data and approved the final manuscript.

Genotyping

Four buccal swabs were obtained for DNA extraction; genotyping of the 37 known CSID-associated variants (S1 Table) was completed by a validated capillary electrophoresis assay (SNaPshot; Laboratory Corporation of America, Research Triangle Park, NC). Intra-assay reproducibility was assessed on 12-sample runs in 3 separate, replicate assays, with samples representing the 37 known hypomorphic variants of the SI gene associated with CSID. The reported prevalence of CSID-associated variants included subjects with simple heterozygous, compound heterozygous, and homozygous SI variant genotypes. Subjects without hypomorphic SI variants did not have any of the 37 analyzed CSID-associated variants on either allele.

The reference for the cumulative prevalence of hypomorphic SI variants in the general population was obtained from the Exome Aggregation Consortium (ExAC) database [15]. As the ExAC database data has now been incorporated into the gnomAD project, the evaluated ExAC data is currently available via a legacy link (https://console.cloud.google.com/storage/browser/gnomad-public/legacy). For this study, SI sequencing data for 32,550 unrelated non-Hispanic white individuals was retrieved from the ExAC database. The ExAC database provides publicly available genetic data from thousands of unrelated individuals of various races/ethnicities, from aggregated disease-specific and population genetic studies. The ExAC database has been used as a control for genetic studies evaluating a wide range of GI disorders, including adult IBS [15–18].

Symptom assessment

Subjects were asked to complete a demographic and symptom questionnaire to capture gender, age, race/ethnicity, and episodes of GI symptoms. All GI symptoms (abdominal pain, diarrhea, excessive flatus) were assessed using a study-specific questionnaire, including frequency, duration, and severity of bowel complaints (S2 Table). The GI symptom burden of the ExAC reference population is unknown.

Stool form was assessed using the modified Bristol Stool Form Scale (BSFS; categories 1–5) for children, with higher scores corresponding to looser stools [19]. The symptom questionnaire was generally given to children aged >7 years, with a parent otherwise providing answers.

Statistical analyses

Results are presented using descriptive statistics, including mean ± standard deviation for continuous data and prevalence and/or percentages for categorical data. The cumulative prevalence of hypomorphic SI variants in this study population was compared with a race/ethnicity-matched ExAC prevalence using the Pearson’s chi-squared test. Reported P-values are one-tailed, and P < .05 was considered statistically significant. Increased risk was estimated using the odds ratio (OR) with a 95% confidence interval (CI).

Results

Population characteristics

Three hundred and eight non-Hispanic white children with chronic, idiopathic, loose stools were enrolled and assessed. There was a slight predominance of boys (58%). Diarrhea, defined as chronic loose stools, was identified as the primary GI symptom.

Prevalence of hypomorphic SI variants

Among the 308 subjects, 14 had at least 1 hypomorphic SI variant, for a prevalence of 4.5%. Study subjects had a statistically significantly higher prevalence of hypomorphic SI variants than the race/ethnicity-matched general population (4.5% vs. 1.3%, P < .01; OR = 3.5; 95% CI: 6.1, 2.0) (Table 1).

Table 1. Relative prevalence of hypomorphic SI variants.

	Study Population		ExAC Population				95% CI
	Number	Prevalence	Number	Prevalence	P-Value	OR	Upper	Lower
Wild-type SI	294	95.5%	32,116	98.7%
Hypomorphic SI variant^a	14	4.5%	434	1.3%
Total	308		32,550		< .01	3.5	6.1	2.1

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^aIncludes one compound heterozygote in the study population.

Thirteen of the 14 subjects with an identified hypomorphic SI variant were simple heterozygous genotypes (93%), and one subject had a compound heterozygous genotype. Five distinct hypomorphic SI variants were identified among these 14 study subjects; 4 of these 5 distinct hypomorphic SI variants are the most common SI variants found in patients diagnosed with CSID (G1073D, V577G, R1124x and F1745C; Table 2) [12]. There were no statistically significant differences between the prevalence of hypomorphic SI variants in male and female subjects (4.5% and 4.7%, respectively).

Table 2. Hypomorphic SI variants identified in the study population.

SI Variants	Rs	Grantham Score^a	Subjects (N = 308)
G1073D^b	121912616	94	7
V577G^b^,^c	121912615	109	5^c
F1745C^b	79717168	205	1
R1124x^b	N/A	N/A	1
I1378S^c	148831941	142	1^c
Total Unique Subjects			14^c

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^aGrantham score is a measure of evolutionary distance in amino acid substitutions, classified by increasing chemical dissimilarity. A higher score reflects a higher likelihood that a substitution will be deleterious based on four general rankings: conservative (0–50), moderately conservative (51–100), moderately radical (101–150), or radical (≥151)

^bOne of the four most common CSID variations

^cOne participant was a compound heterozygote with both a V577G and an I1378S variant.

Symptom burden associated with hypomorphic SI variants

Mean differences in the symptom burden of subjects with a hypomorphic SI variant versus subjects without a hypomorphic SI variant are reported in Table 3. Compared with the 294 subjects without a hypomorphic SI variant, the 14 with a hypomorphic SI variant had significantly more frequent GI symptoms, including: more frequent weekly episodes of loose stools (P < .01), higher daily overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). Subjects with a hypomorphic SI variant also were younger (P < .01).

Table 3. Symptom burden of study subjects by SI genotype.

	Total study population	With Hypo-morphic SI Variant	Without Hypo-morphic SI Variants	Mean Difference	P-value
Study subjects	308	14	294
Age (mean yr)	7.6	3.8	7.7	4.0	< .01
Symptom Burden (mean)
Symptom duration (mo)	8.8	8.6	8.9	0.3	NS
Diarrhea episode (d/wk)	5.1	6.6	5.0	1.6	< .01
Stools (#/d)	3.4	5.3	3.3	1.9	< .01
Pediatric BSFS, last diarrheal event	4.3	4.7	4.3	0.4	.01
2Abdominal pain (d/wk)	3.6	3.6	3.6	——	NS
Pain events (#/d)	1.4	1.4	1.4	——	NS
Pain severity (6-point VAS)	2.4	2.4	2.4	——	NS
Gas (d/wk)	4.9	6.3	4.9	1.4	.02
Gas events (#/d)	1.9	2.1	1.9	0.3	NS

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BSFS, modified Bristol Stool Form Scale for children (categories 1–5, higher scores corresponding to looser stools); NS, not statistically significant; VAS, visual analog scale, 0–5

Discussion

We found hypomorphic SI variants among a study population of non-Hispanic white children with chronic, idiopathic, loose stools. The prevalence of these known hypomorphic SI variants was significantly higher in this study population compared to a race/ethnicity-matched general population. In addition, study subjects with a hypomorphic SI variant had a greater GI symptom burden than study subjects without hypomorphic SI variants. These findings add to the growing evidence suggesting heterozygous SI hypomorphic variants are associated with the development of CSID-associated GI symptoms.

The most common hypomorphic SI variants in our study cohort were also the hypomorphic SI variants most commonly identified in other genetic studies of individuals diagnosed with CSID [12]. Although the biochemical and functional effects of several SI variants have been well characterized and found to diminish sucrase and isomaltase function [4, 5, 8], the potential effect of a heterozygous genotype of a hypomorphic SI variant is still being studied and remains to be fully elucidated. Using either the duodenal disaccharidase enzyme assay or the ¹³C breath test to determine the extent of sucrase enzyme activity, family members of patients with CSID (with either presumed or well-documented heterozygosity for a hypomorphic SI variant) have been found to have decreased sucrase enzyme activity [14, 20]. Further supporting the potential pathobiological effect of heterozygous genotypes of hypomorphic SI variants are recent findings by Henström et al and Garcia-Etxebarria et al, who reported that heterozygous SI gene variants may be associated with an increased risk for diagnosis of adult IBS [15, 16]. Nevertheless, further prospective clinical evaluations including identification of heterozygous hypomorphic SI variants, functional measurements of sucrase-isomaltase (e.g., enzyme assays), controlled dietary exposures, and basic cellular and molecular based studies are needed to more clearly determine the role of hypomorphic SI heterozygous genotypes.

Identifying the underlying factors contributing to functional GI symptoms is important as this knowledge may lead to more effective therapies. Children with CSID have been shown to benefit from a sucrose-restricted diet and enzyme replacement therapy with sacrosidase taken with meals [21–24]. Gastrointestinal symptoms related to diminished sucrase-isomaltase activity are primarily correlated with factors such as the extent of functional intestinal enzyme activity present and the amount of sucrose and/or starch ingested [4, 13]. It should be noted that in one study, a child with a heterozygous genotype of a hypomorphic SI variant, who was a sibling of a CSID-diagnosed subject, was asymptomatic [10]. Future studies in this area may consider assessing both enzyme activity and dietary intake relative to SI hypomorphic variants and the associated GI symptom burden.

There are a few limitations to this study. One limitation is that the age-, gender-, and race/ethnicity-matched control population was not actively recruited. However, even though the GI symptoms associated with the database entries are unknown, the ExAC reference database of a significantly large population allowed for a race/ethnicity-matched comparison. Second, the entire SI gene was not sequenced in participants. This opens the possibility–however unlikely–that some of the study subjects identified as lacking a hypomorphic SI variant had one or more hypomorphic SI variants in an uninvestigated portion of the SI gene. In addition, some of the study subjects identified as having a simple heterozygous genotype of a hypomorphic SI variant may also have a hypomorphic SI variant in an uninvestigated portion of the SI gene.

There are several strengths in the study. First, this multicenter effort was, to our knowledge, the largest of its kind in children with functional GI symptoms. Second, SI genotyping focused on 37 CSID-associated SI variants that have been well characterized biochemically as hypomorphic in prior studies. This leads to greater plausibility of the results. Third, the study was conducted in various academic and private practice settings, which will lead to greater generalizability of our findings.

Conclusion

In conclusion, we found CSID-associated hypomorphic SI variants in a study population of non-Hispanic white children with chronic, idopathic, loose stools. These CSID-associated hypomorphic SI variants were found to occur at a significantly higher prevalence than that reported in a race/ethnicity-matched reference population. Subjects with hypomorphic SI variants had more GI symptoms of frequent diarrhea and gas, a higher stool frequency, and looser stools compared to those in the study population without hypomorphic SI variants.

Supporting information

S1 Table. Hypomorphic SI Variants Identified in children with chronic gastrointestinal symptoms.

Ala, alanine; Arg, arginine; Asp, aspartate; Cys, cysteine; Gln, glutamine; Glu, glutamate; Gly, glycine; I, isomaltase; Ile, isoleucine; Leu, leucine; N/A, not available; Phe, phenylalanine Pro, proline; S, sucrase; Ser, serine; Thr, threonine; Tyr, tyrosine; Trp, tryptophan; Val, valine.

(DOCX)

Click here for additional data file.^{(33.9KB, docx)}

S2 Table. Study questionnaire.

(DOCX)

Click here for additional data file.^{(270KB, docx)}

S1 Data

(XLSX)

Click here for additional data file.^{(65.5KB, xlsx)}

Acknowledgments

We would like to acknowledge all investigators, coordinators, and study site personnel, as well as patients and their families for their participation in this study.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

QOL Medical, LLC (https://www.qolmed.com/), funded the entire study. The funders participated in the study design, analyses, and critical review of the manuscript but had no role in data collection, decision to publish, or preparation of the manuscript.

References

1.Chumpitazi BP, Shulman RJ. Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome. Mol Cell Pediatr. 2016;3(1):11 10.1186/s40348-016-0036-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional disorders: children and adolescents. Gastroenterology. 2016;150(6):1456–68. 10.1053/j.2016.02015 [DOI] [PubMed] [Google Scholar]
3.Naim HY, Roth J, Sterchi EE, Lentze M, Milla P, Schmitz J, et al. Sucrase-isomaltase deficiency in humans. Different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme. J Clin Invest. 1988;82(2):667–79. 10.1172/JCI113646 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Naim HY, Heine M, Zimmer KP. Congenital sucrase-isomaltase deficiency: heterogeneity of inheritance, trafficking, and function of an intestinal enzyme complex. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S13–20. 10.1097/01.mpg.0000421402.57633.4b [DOI] [PubMed] [Google Scholar]
5.Alfalah M, Keiser M, Leeb T, Zimmer KP, Naim HY. Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency. Gastroenterology. 2009;136(3):883–92. 10.1053/j.gastro.2008.11.038 [DOI] [PubMed] [Google Scholar]
6.Gericke B, Amiri M, Naim HY. The multiple roles of sucrase-isomaltase in the intestinal physiology. Mol Cell Pediatr. 2016;3(1):2 10.1186/s40348-016-0033-y [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Jacob R, Zimmer KP, Schmitz J, Naim HY. Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme. J Clin Invest. 2000;106(2):281–7. 10.1172/JCI9677 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Keiser M, Alfalah M, Pröpsting MJ, Castelletti D, Naim HY. Altered folding, turnover, and polarized sorting act in concert to define a novel pathomechanism of congenital sucrase-isomaltase deficiency. J Biol Chem. 2006;281(20):14393–9. 10.1074/jbc.M513631200 [DOI] [PubMed] [Google Scholar]
9.Ritz V, Alfalah M, Zimmer KP, Schmitz J, Jacob R, Naim HY. Congenital sucrase-isomaltase deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum. Gastroenterology. 2003;125(6):1678–85. 10.1053/j.gastro.2003.09.022 [DOI] [PubMed] [Google Scholar]
10.Sander P, Alfalah M, Keiser M, Korponay-Szabo I, Kovács JB, Leeb T, et al. Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption. Human Mutat. 2006;27(1):119 10.1002/humu.9392 [DOI] [PubMed] [Google Scholar]
11.Spodsberg N, Jacob R, Alfalah M, Zimmer KP, Naim HY. Molecular basis of aberrant apical protein transport in an intestinal enzyme disorder. J Biol Chem. 2001;276(26):23506–10. 10.1074/jbc.C100219200 [DOI] [PubMed] [Google Scholar]
12.Uhrich S, Wu Z, Huang JY, Scott CR. Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S34–5. 10.1097/01.mpg.0000421408.65257.b5 [DOI] [PubMed] [Google Scholar]
13.Treem WR. Clinical aspects and treatment of congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S7–13. 10.1097/01.mpg.0000421401.57633.9 [DOI] [PubMed] [Google Scholar]
14.Chumpitazi BP, Robayo-Torres CC, Opekun AR, Nichols Bl Jr, Naim HY. Congenital sucrase-isomaltase deficiency: summary of an evaluation in one family. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S36 10.1097/01.mpg.0000421409.65257.fc [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Henström M, Diekmann L, Bonfiglio F, Hadizadeh F, Kuech EM, von Köckritz-Blickwede M, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2018;67(2):263–70. 10.1136/gutjnl-2016-312456 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Garcia-Etxebarria K, Zheng T, Bonfiglio F, Bujanda L, Dlugosz A, Lindberg G, et al. Increased prevalence of rare sucrase-isomaltase pathogenic variants in irritable bowel syndrome patients. Clin Gastroenterol Hepatol. 2018;16(10):1673–76. 10.1016/j.cgh.2018.01.047 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Nouhravesh N, Ahlberg G, Ghouse J, Andreasen C, Svendsen JH, Haunsø S, et al. Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy. Mol Genet Genomic Med. 2016;4(6):617–23. 10.1002/mgg3.245 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Tarailo-Graovac M, Zhu JYA, Matthews A, Wasserman WW. Assessment of the ExAC data set for the presence of individuals with pathogenic genotypes implicated in severe Mendelian pediatric disorders. Genet Med. 2017;19(12):1300–8. 10.1038/gim.2017.50 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Chumpitazi BP, Lane MM, Czyzewski DI, Weidler EM, Swank PR, Shulman RJ. Creation and initial evaluation of a Stool Form Scale for children. J Pediatr. 2010;157(4):594–7. 10.1016/j.jpeds.2010.04.040 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Opekun AR, Balesh AM, Shelby HT. Use of the biphasic ¹³C-sucrose/glucose breath test to assess sucrose maldigestion in adults with functional bowel disorders. Biomed Res Int. 2016;2016:7952891 10.1155/2016/7952891 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Treem WR, Ahsan N, Sullivan B, Rossi T, Holmes R, Fitzgerald J, et al. Evaluation of liquid yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency. Gastroenterology. 1993;105(4):1061–8. 10.1016/0016-5085(93)90950-h [DOI] [PubMed] [Google Scholar]
22.Treem WR, McAdams L, Stanford L, Kastoff G, Justinich C, Hyams J. Sacrosidase therapy for congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 1999;28(2):137–42. 10.1097/00005176-199902000-00008 [DOI] [PubMed] [Google Scholar]
23.McMeans AR. Congenital sucrase-isomaltase deficiency: diet assessment and education guidelines. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S37–9. 10.1097/01.mpg.0000421410.72880.ae [DOI] [PubMed] [Google Scholar]
24.Lücke T, Keiser M, Illsinger S, Lentze MJ, Naim HY, Das AM. Congenital and putatively acquired forms of sucrase-isomaltase deficiency in infancy: effects of sacrosidase therapy. J Pediatr Gastroenterol Nutr. 2009;49(4):485–7. 10.1097/MPG.0b013e3181a4c0df [DOI] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0231891.r001

Decision Letter 0

Adriana Calderaro

31 Jan 2020

PONE-D-19-34036

Hypomorphic SI genetic variants are associated with childhood chronic loose stools

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: The manuscript compiles the results of a large multicenter study on the relation between functional GI symptoms in children and 37 variants of the sucrase-isomaltase gene that have been previously characterized at the biochemical and cellular levels in congenital sucrase-isomaltase deficiency (CSID). The study demonstrates a significantly higher prevalence of hypomorphic SI variants in the cases studied than in the general population.

The study supports recent views that heterozygous genotype of hypomorphic SI may be associated with an increased risk of irritable bowel syndrome. The study is properly conducted and impressive in terms of the number of cases studied. The statistical analyses are convincing and the conclusions are sound. The manuscript is clearly written (only lines 95/96 should be rewritten).

I fully agree with the conclusions, have no points of criticism and recommend the acceptance of the manuscript in its present form.

Reviewer #2: The manuscript by Chumpitazi et al assesses the prevalence of variants in the sucrase-isomaltase gene among a cohort of children with chronic diarrhea. The authors find that confirmed or predicted loss of function mutations are more prevalent in the studied population versus a the EXAC reference genomic database. Furthermore, they show that patients with mutations have more diarrhea symptoms than the rest of the patient cohort. The study suggests a potentially interesting possible association between mild chronic diarrhea and SI function in young children. The strengths of the paper are that the patient cohort is taken from multiple different centers / sites and sample genotyping was done in a uniform manner at a central site. The statistics and results, while limited in scope are appropriately done.

1. The major limitation in understanding the significance of these findings, as briefly but insufficiently discussed, is that the functional effect of heterozygosity in the various loss-of-function mutations, and especially the common variants found in these patients remain poorly described and essentially unknown. The authors cite a single case report and a study on 13C breath testing in functional GI disorders (not specifically with known SI genotype), neither of which is sufficient to address the question of SI heterozygosity and enzyme activity. To assess the functional significance requires prospective clinical studies with functional measurements (enzyme/breath testing) correlated to genotype as well as basic cell-based studies assessing heterozygous vs homozygous mutations and function / localization. This should be more clearly part of the discussion and the major limitations of the existing literature (studies of symptom correlation rather than objective enzyme activity, few studies, no cellular studies etc) more straightforwardly stated.

2. In the methods the reference database link should be updated to either Gnomad or the legacy EXAC only data. There should be brief sentence explaining this update.

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PLoS One. 2020 May 20;15(5):e0231891. doi: 10.1371/journal.pone.0231891.r002

Author response to Decision Letter 0

3 Apr 2020

I fully agree with the conclusions, have no points of criticism and recommend the acceptance of the manuscript in its present form.

We thank the Reviewer for his/her highly supportive comments of the manuscript. We have rewritten lines 95-96 as requested.

We thank the Reviewer for his/her supportive comments and critiques of the manuscript. We agree that the functional effect of heterozygosity for the identified mutations needs to be further elucidated. We have edited the Discussion within the manuscript to more clearly delineate the need for further investigation.

2. In the methods the reference database link should be updated to either Gnomad or the legacy EXAC only data. There should be brief sentence explaining this update.

We have updated the reference database link and provided an explanation for the update

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(13.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0231891.r003

Decision Letter 1

Adriana Calderaro

3 Apr 2020

Hypomorphic SI genetic variants are associated with childhood chronic loose stools

PONE-D-19-34036R1

Dear Dr. Chumpitazi,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: My initial review recommended acceptance of the manuscript as it stands and I have just asked for minor edits. These edits have been made in the revised version.

Reviewer #2: (No Response)

**********

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Reviewer #1: No

Reviewer #2: No

PLoS One. doi: 10.1371/journal.pone.0231891.r004

Acceptance letter

Adriana Calderaro

8 May 2020

PONE-D-19-34036R1

Hypomorphic SI genetic variants are associated with childhood chronic loose stools

Dear Dr. Chumpitazi:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Hypomorphic SI Variants Identified in children with chronic gastrointestinal symptoms.

(DOCX)

Click here for additional data file.^{(33.9KB, docx)}

S2 Table. Study questionnaire.

(DOCX)

Click here for additional data file.^{(270KB, docx)}

S1 Data

(XLSX)

Click here for additional data file.^{(65.5KB, xlsx)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(13.5KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

[pone.0231891.ref001] 1.Chumpitazi BP, Shulman RJ. Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome. Mol Cell Pediatr. 2016;3(1):11 10.1186/s40348-016-0036-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref002] 2.Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional disorders: children and adolescents. Gastroenterology. 2016;150(6):1456–68. 10.1053/j.2016.02015 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref003] 3.Naim HY, Roth J, Sterchi EE, Lentze M, Milla P, Schmitz J, et al. Sucrase-isomaltase deficiency in humans. Different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme. J Clin Invest. 1988;82(2):667–79. 10.1172/JCI113646 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref004] 4.Naim HY, Heine M, Zimmer KP. Congenital sucrase-isomaltase deficiency: heterogeneity of inheritance, trafficking, and function of an intestinal enzyme complex. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S13–20. 10.1097/01.mpg.0000421402.57633.4b [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref005] 5.Alfalah M, Keiser M, Leeb T, Zimmer KP, Naim HY. Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency. Gastroenterology. 2009;136(3):883–92. 10.1053/j.gastro.2008.11.038 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref006] 6.Gericke B, Amiri M, Naim HY. The multiple roles of sucrase-isomaltase in the intestinal physiology. Mol Cell Pediatr. 2016;3(1):2 10.1186/s40348-016-0033-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref007] 7.Jacob R, Zimmer KP, Schmitz J, Naim HY. Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme. J Clin Invest. 2000;106(2):281–7. 10.1172/JCI9677 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref008] 8.Keiser M, Alfalah M, Pröpsting MJ, Castelletti D, Naim HY. Altered folding, turnover, and polarized sorting act in concert to define a novel pathomechanism of congenital sucrase-isomaltase deficiency. J Biol Chem. 2006;281(20):14393–9. 10.1074/jbc.M513631200 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref009] 9.Ritz V, Alfalah M, Zimmer KP, Schmitz J, Jacob R, Naim HY. Congenital sucrase-isomaltase deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum. Gastroenterology. 2003;125(6):1678–85. 10.1053/j.gastro.2003.09.022 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref010] 10.Sander P, Alfalah M, Keiser M, Korponay-Szabo I, Kovács JB, Leeb T, et al. Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption. Human Mutat. 2006;27(1):119 10.1002/humu.9392 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref011] 11.Spodsberg N, Jacob R, Alfalah M, Zimmer KP, Naim HY. Molecular basis of aberrant apical protein transport in an intestinal enzyme disorder. J Biol Chem. 2001;276(26):23506–10. 10.1074/jbc.C100219200 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref012] 12.Uhrich S, Wu Z, Huang JY, Scott CR. Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S34–5. 10.1097/01.mpg.0000421408.65257.b5 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref013] 13.Treem WR. Clinical aspects and treatment of congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S7–13. 10.1097/01.mpg.0000421401.57633.9 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref014] 14.Chumpitazi BP, Robayo-Torres CC, Opekun AR, Nichols Bl Jr, Naim HY. Congenital sucrase-isomaltase deficiency: summary of an evaluation in one family. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S36 10.1097/01.mpg.0000421409.65257.fc [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref015] 15.Henström M, Diekmann L, Bonfiglio F, Hadizadeh F, Kuech EM, von Köckritz-Blickwede M, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2018;67(2):263–70. 10.1136/gutjnl-2016-312456 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref016] 16.Garcia-Etxebarria K, Zheng T, Bonfiglio F, Bujanda L, Dlugosz A, Lindberg G, et al. Increased prevalence of rare sucrase-isomaltase pathogenic variants in irritable bowel syndrome patients. Clin Gastroenterol Hepatol. 2018;16(10):1673–76. 10.1016/j.cgh.2018.01.047 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref017] 17.Nouhravesh N, Ahlberg G, Ghouse J, Andreasen C, Svendsen JH, Haunsø S, et al. Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy. Mol Genet Genomic Med. 2016;4(6):617–23. 10.1002/mgg3.245 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref018] 18.Tarailo-Graovac M, Zhu JYA, Matthews A, Wasserman WW. Assessment of the ExAC data set for the presence of individuals with pathogenic genotypes implicated in severe Mendelian pediatric disorders. Genet Med. 2017;19(12):1300–8. 10.1038/gim.2017.50 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref019] 19.Chumpitazi BP, Lane MM, Czyzewski DI, Weidler EM, Swank PR, Shulman RJ. Creation and initial evaluation of a Stool Form Scale for children. J Pediatr. 2010;157(4):594–7. 10.1016/j.jpeds.2010.04.040 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref020] 20.Opekun AR, Balesh AM, Shelby HT. Use of the biphasic ¹³C-sucrose/glucose breath test to assess sucrose maldigestion in adults with functional bowel disorders. Biomed Res Int. 2016;2016:7952891 10.1155/2016/7952891 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0231891.ref021] 21.Treem WR, Ahsan N, Sullivan B, Rossi T, Holmes R, Fitzgerald J, et al. Evaluation of liquid yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency. Gastroenterology. 1993;105(4):1061–8. 10.1016/0016-5085(93)90950-h [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref022] 22.Treem WR, McAdams L, Stanford L, Kastoff G, Justinich C, Hyams J. Sacrosidase therapy for congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 1999;28(2):137–42. 10.1097/00005176-199902000-00008 [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref023] 23.McMeans AR. Congenital sucrase-isomaltase deficiency: diet assessment and education guidelines. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S37–9. 10.1097/01.mpg.0000421410.72880.ae [DOI] [PubMed] [Google Scholar]

[pone.0231891.ref024] 24.Lücke T, Keiser M, Illsinger S, Lentze MJ, Naim HY, Das AM. Congenital and putatively acquired forms of sucrase-isomaltase deficiency in infancy: effects of sacrosidase therapy. J Pediatr Gastroenterol Nutr. 2009;49(4):485–7. 10.1097/MPG.0b013e3181a4c0df [DOI] [PubMed] [Google Scholar]

PERMALINK

Hypomorphic SI genetic variants are associated with childhood chronic loose stools

Bruno P Chumpitazi

Jeffery Lewis

Derick Cooper

Mauro D’Amato

Joel Lim

Sandeep Gupta

Adrian Miranda

Natalie Terry

Devendra Mehta

Ann Scheimann

Molly O’Gorman

Neelesh Tipnis

Yinka Davies

Joel Friedlander

Heather Smith

Jaya Punati

Julie Khlevner

Mala Setty

Carlo Di Lorenzo

Roles

Abstract

Objective

Methods

Results

Conclusion

Introduction

Methods

Study design and subjects

Genotyping

Symptom assessment

Statistical analyses

Results

Population characteristics

Prevalence of hypomorphic SI variants

Table 1. Relative prevalence of hypomorphic SI variants.

Table 2. Hypomorphic SI variants identified in the study population.

Symptom burden associated with hypomorphic SI variants

Table 3. Symptom burden of study subjects by SI genotype.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Adriana Calderaro

Roles

Author response to Decision Letter 0

Decision Letter 1

Adriana Calderaro

Roles

Acceptance letter

Adriana Calderaro

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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