New insights into the pathogenic variation landscape in pediatric gastroenterology diseases

Abstract

Pediatric gastrointestinal (GI) diseases often present with overlapping clinical manifestations. However, invasive diagnostic procedures such as tissue biopsies are substantially more challenging to conduct in children than in adults, which may hinder timely diagnosis and treatment. This editorial addresses the study of Alsarhan et al recently published a study in World Journal of Gastroenterology, who retrospectively examined 69 Middle Eastern pediatric patients with GI diseases. The study combined whole exome sequencing and chromosomal microarray analysis of data from the Greater Middle East Variome database, which revealed that 64.4% of patients with GI diseases carried autosomal recessive genetic variants, with a remarkable 55% diagnostic yield, and informed therapeutic adjustments for 97% of the pediatric patients who tested positive for genetic diseases. Nevertheless, the study also has several limitations, specifically, a small sample size, specimen type ambiguity, inconsistent evidence of candidate genes for therapy, and lack of reporting on differences in pathogenic genetic variation sites between populations. Overall, the study of Alsarhan et al demonstrates that in populations with a high prevalence of hereditary diseases, genetic testing can facilitate clinical diagnosis and the development of precision treatment plans.

Key Words: Limitations; Insights; NR1I3; Pediatric gastrointestinal disease; Strengths of genetic testing

Core Tip: Alsarhan et al recently published a study concerning clinical utility of genomic investigations in a pediatric gastroenterology disease cohort in the World Journal of Gastroenterology. In order to know their contribution, in the present editorial, we reviewed their work and compare it with similar full-length English-language publications in PubMed.

This editorial refers to “Clinical utility of genomic investigations in a Middle Eastern pediatric gastroenterology disease cohort” by Alsarhan et al, 2026; https://doi.org/10.3748/wjg.v32.i13.115810.

---

INTRODUCTION

The ability of genomics to aid in the diagnosis of gastrointestinal (GI) diseases varies with clinical presentation and has been extensively investigated[1]. For example, younger age was reported to be associated with higher odds of receiving a positive genetic test result for pediatric inflammatory bowel disease[2]. Several studies have demonstrated the value of genetics testing for clinical diagnosis and precision treatment of GI diseases. Extending on previous findings published in World Journal of Gastroenterology, Alsarhan et al[3] explored the utility of genomic testing in diagnosing conditions in a pediatric cohort of Middle Eastern individuals with GI diseases. They reported that in all disease groups [overall positive diagnostic yield of 55% (38/69)], the diagnostic yield was highest in patients with chronic diarrhea [73.3% (11/15)], whereas the diagnostic yields in patients with pancreatitis and failure to thrive were 50% each (2/4 and 4/8, respectively). These findings warrant further investigation.

The present editorial reviewed the study of Alsarhan et al[3] and compared the findings with those of similar full-length English-language articles indexed in PubMed between January 1, 2021, and December 31, 2025. We excluded review articles, editorials, and meta-analyses from our investigation. Our findings elucidate the link between genetic testing and clinical diagnosis in patients with chronic diarrhea and patients with pancreatitis.

PATIENTS WITH CONGENITAL DIARRHEA

Our search of the literature yielded nine articles on patients with chronic diarrhea[3-12] (Table 1). As indicated in Table 1, in the six ethnic groups (children from the United Arab Emirates, China, India, Türkiye, Ireland, and Pakistan) with chronic diarrhea, mutations were observed in 14 genes (EPCAM, SLC26A3, MYO5B, SPINT2, PAH, NLRP12, FOXP3, TTC37, RFXANK, MEFV, PERCC1, SKIC2, SKIC3, and DGAT1). Of these, mutations of SPINT2, PAH, and NLRP12 were only observed in patients from the United Arab Emirates; mutations of FOXP3 were only observed in patients from China; mutations of RFXANK, MEFV, and SKIC2 occurred only in patients from Türkiye; mutations of PERCC1 occurred only in patients from Ireland; and DGAT1 deficiency was reported only in patients from Pakistan. Table 2 presents the diagnostic yield of genetic tests in the nine articles, which ranged from 75.0% to 100%. These results indicate that the diagnostic yield (73.3%) reported in the study of Alsarhan et al[3] is reasonable.

Table 1 Genetic analysis of children with chronic diarrhea in the study of Alsarhan et al[3] and nine similar articles published between January 1, 2021, and December 31, 2025.

Genes	Ethnics	Ref.
EPCAM	United Arab Emirates, Indian, Chinese	Alsarhan et al[3]; Yan et al[4]; Mantoo et al[6]; Wang et al[11]
SLC26A3	United Arab Emirates, Chinese	Alsarhan et al[3]; Yan et al[4]
MYO5B	United Arab Emirates, Chinese, Indian, Turk	Alsarhan et al[3]; Yan et al[4]; Mantoo et al[6]; Cakir et al[7]
SPINT2	United Arab Emirates	Alsarhan et al[3]
PAH	United Arab Emirates	Alsarhan et al[3]
NLRP12	United Arab Emirates	Alsarhan et al[3]
FOXP3	Chinese	Wu et al[5]
TTC37	Indian, Turk	Mantoo et al[6]; Cakir et al[7]
RFXANK	Turk	Cakir et al[7]
MEFV	Turk	Cakir et al[7]
PERCC1	Irish	Marek-Yagel et al[8]
SKIC2	Turk	Ozturk et al[9]
SKIC3	Turk, United Arab Emirates	Ozturk et al[9]; Alrammal et al[10]
DGAT1 deficiency	Pakistani	Mehmood et al[12]

Table 2 Genetic diagnostic yield in children with chronic diarrhea in the study of Alsarhan et al[3] and nine similar articles published between January 1, 2021, and December 31, 2025.

Ref.	Alsarhan et al[3]	Yan et al[4]	Wu et al[5]	Mantoo et al[6]	Cakir et al[7]	Marek-Yagel et al[8]	Ozturk et al[9]	Alrammal et al[10]	Wang et al[11]	Mehmood et al[12]
Diagnostic yield (%)	73.3 (11/15)	100 (4/4)	100 (1/1)	75.0 (3/4)	87.5 (14/16)	100 (2/2)	100 (8/8)	100 (1/1)	100 (1/1)	100 (1/1)

As indicated in Table 1, mutations of the MYO5B gene were reported in children from the United Arab Emirates, China, India, and Türkiye[3,4,6,7]. However, the mutation sites in these children differed (Table 3). Of the three neonates from the United Arab Emirates that were considered, two received a diagnosis of tufting enteropathy and carried a homozygous c.1966C>T (p.Arg656Cys) mutation (missense mutation) of the MYO5B gene; the remaining neonate received a diagnosis of microvillous inclusion disease (MVID) (a life-threatening condition) and carried a homozygous c.82del (p.Thr28Profs47) mutation (frameshift mutation; Table 1 and Table 3[3]). By contrast, the Chinese patient carried compound heterozygous mutations [a heterozygous c.1306G>T (p.Val436Phe) and a heterozygous c.3190C>T (p.Arg1064, nonsense mutation)] and had severe symptoms (stools were watery and evacuated more than 10 times per day)[4]. The Indian patient received a diagnosis of MVID and carried a heterozygous c.1952C>G (p.Thr651Arg) mutation; the genetic mutation in this patient was interpreted as a “variant of uncertain significance”[6]. The two Turkish patients also received a diagnosis of MVID, and they carried a homozygous c.2014A>T (p.Lys672, nonsense mutation) and a homozygous c.1323-2A>G (canonical splice-site destroyed mutation), respectively[7]. These results suggest that mutation type is correlated with disease severity: The clinical manifestations were more severe in the patients with frameshift mutations, nonsense mutations, or canonical splice-site destroyed mutations than in those with missense mutations.

Table 3 Genetic mutation of MYO5B in children with chronic diarrhea of different ethnic groups.

	UAE[3]	Chinese[4]	Indian[6]	Turk[7]
MYO5B	Homozygous c.1966C>T (p.Arg656Cys1), homozygous c.82del p.(Thr28Profs47) (frameshift mutation2)	Heterozygous c.1306G>T (p.Val436Phe) plus heterozygous c.3190C>T (p.Arg1064) (nonsense mutation3)	Heterozygous c.1952C>G (p.Thr651Arg4)	Homozygous c.2014A>T (p.Lys672, nonsense mutation5), homozygous c.1323-2A>G (canonical splice-site destroyed mutation5)

¹Received a diagnosis of tufting enteropathy.

²Had microvillous inclusion disease (a life-threatening condition).

³Had severe symptoms (stools were watery and evacuated more than 10 times per day).

⁴Microvillous inclusion disease (variant of uncertain significance).

⁵Microvillous inclusion disease.

PATIENTS WITH HEREDITARY PANCREATITIS

Our search of the literature initially yielded eight articles reporting genetic tests on patients with pancreatitis[13-20]. Of these, two reported the observational research on the effect of an Ayurvedic treatment protocol in patients of hereditary pancreatitis and comments on pancreatic enzyme use reduces pancreatitis frequency, respectively[19,20]; they did not address genetic mutations. Consequently, they were excluded from the analysis. As indicated in Table 4, of the six ethnic groups represented in the remaining studies (children from the United Arab Emirates, India, Italy, Japan, the United States, and Brazil) with hereditary pancreatitis, genetic mutations were observed in seven genes (PRSS1, CTRC, CFTR, SPINK1, chymotrypsin C, cathepsin B, and CaSR)[3,13-18]. Of these genes, PRSS1, CFTR, and SPINK1 were each observed in a distinct ethnic population.

Table 4 Genetic analysis of patients with pancreatitis in the study of Alsarhan et al[3] and six similar articles published between January 1, 2021, and December 31, 2025.

Genes	PRSS1	CTRC	CFTR	SPINK1	Chymotrypsin C	Cathepsin B	CaSR
Ethnics	United Arab Emirates1, Indians2, Italians3	United Arab Emirates4	Japanese5, Americans6, Italians7	Indians8, Italians9, Brazilians10	Indians11	Indians12	Italians13
Ref.	Alsarhan et al[3]; Prakash et al[15]; Destro et al[18]	Alsarhan et al[3]	Fujita et al[13]; Son et al[14]; Bontempo et al[16]	Prakash et al[15]; Bontempo et al[16]; Solis-Pazmino et al[17]	Prakash et al[15]	Prakash et al[15]	Bontempo et al[16]

¹p.Arg122His.

²p.Arg122His.

³p.Asn29Ile.

⁴p.Lys247-Arg254del.

⁵Three heterozygous mutations (p.Thr1220Ile, p.Arg1453Trp, and p.Val470Met).

⁶Heterozygous mutation (p.Asn1303 Lys).

⁷p.Leu997Phe.

⁸p.Asn34Ser.

⁹p.Ile73Phe.

¹⁰p.Asn34Ser.

¹¹p.Ala16Val.

¹²p.Asp22Gly.

¹³p.Phe790Ser.

Table 4 reveals that all identified variants in the children with pancreatitis were missense mutations, specifically, heterozygous mutations, compound heterozygous mutations, and homozygous mutations, with the exception of the mutation in one patient from the United Arab Emirates who carried a c.738761del [p.(Lys247Arg254del) in-frame deletion] in the CTRC gene. The clinical manifestations (recurrent pancreatitis) were notably more severe in this patient than were those (chronic pancreatitis) in the other patient from the United Arab Emirates, who carried a p.Arg122His (missense mutation) in the PRSS1 gene (Table 1). As reported in Table 5, with the exception of the study of Alsarhan et al[3], all of the publications reported on a single patient with pancreatitis who received a diagnosis of a genetic condition, resulting in diagnostic yields of 100% (1/1) in each study. However, individual case reports are subject to publication bias; hence, although the diagnostic yields were 100%, the findings were not directly comparable to those of cohort studies.

Table 5 Genetic diagnostic yield for patients with pancreatitis in the study of Alsarhan et al[3] and six similar articles published between January 1, 2021, and December 31, 2025.

Ref.	Alsarhan et al[3]	Fujita et al[13]	Son et al[14]	Prakash et al[15]	Bontempo et al[16]	Solis-Pazmino et al[17]	Destro et al[18]
Diagnostic yield (%)	50.0 (2/4)	100 (1/1)	100 (1/1)	100 (1/1)	100 (1/1)	100 (1/1)	100 (1/1)

STRENGTHS OF ALSARHAN ET AL

Robust clinical sequencing methodology

Alsarhan et al[3] adopted a highly reliable sequencing workflow. Ultrasonic cleavage provided more uniform and random genome coverage than enzymatic cleavage could, enabling precise DNA fragmentation. Furthermore, the use of the industry-standard Agilent Clinical Research Exome V2 kit facilitated comprehensive evaluation of clinically relevant pathogenic loci. Notably, the reported minimum mean depth of 100 × strictly adhered to the 2015 American College of Medical Genetics and Genomics guidelines for high-quality clinical germline variant diagnosis.

Synergistic application of whole exome sequencing and chromosomal microarray analysis

A major strength of the study of Alsarhan et al[3] is its combination of whole exome sequencing (WES) and chromosomal microarray analysis (CMA). WES is highly effective in detecting small insertions or deletions and single-nucleotide variants, whereas CMA is superior in identifying large-scale copy number variations. Notably, Alsarhan et al[3] reported that 12 patients with very early onset inflammatory bowel disease did not receive a diagnosis after specialized gene panels were used to test for the condition, which was only identified through a combination of WES and CMA. This result suggests that integrating WES and CMA can substantially reduce the risk of false-negative results in clinical genomics.

Clinical utility

The findings of Alsarhan et al[3] informed therapeutic adjustments for 97% of the patients in the study who tested positive for genetic diseases, demonstrating that genetic testing can help optimize the management of monogenic inflammatory bowel disease. Nevertheless, additional longitudinal studies are required to verify whether the reported treatment modifications increase survival rates and long-term clinical outcomes and to validate genetic testing as an aid for transitioning clinical management from symptom control to curative intervention.

Population-specific genetic insights

The study of Alsarhan et al[3] integrated data from the Greater Middle East Variome database. By revealing that 64.4% of patients with GI diseases had autosomal recessive genetic variants, their study established a strong link between GI disease and high rates of consanguinity in the Middle East. This observation is consistent with the genomic landscape described in Nature Genetics[21] and highlights the utility of population-specific genomic references.

LIMITATIONS

Sample size

As acknowledged by Alsarhan et al[3], their cohort of 69 patients was small. Consequently, in subgroups such as those of patients with pancreatitis (n = 4) or polyposis (n = 2), the sample size was insufficient to support generalizable conclusions.

Specimen type ambiguity

The study did not specify the primary specimen type used in DNA extraction. This information is crucial because in cases of very early onset inflammatory bowel disease or liver failure, germline variants identified through tissue biopsies may be confounded by somatic mosaicism. Additionally, exclusive reliance on peripheral blood samples does not account for tissue-specific genetic alterations.

Novel candidate genes for therapy

The study’s discovery of a 4-bp deletion in NR1I3 (p.Ser107Argfs6) in a patient with cholestasis is promising. However, the presence of the same homozygous deletion in asymptomatic family members of the patient indicates that this deletion is not always pathogenic. Therefore, additional functional studies are required to verify the pathogenicity of this variant.

Genetic variation sites contributing to disease

In neonatal hyperbilirubinemia, the key variation site of the UGT1A1 gene is c.-41-40dupTA (at the promoter area of the gene) in Middle Eastern patients, as observed by Alsarhan et al[3] (Table 1). This site is also implicated in neonatal hyperbilirubinemia in White male patients[22]. By contrast, in Asian individuals, the key variation site is c.211G>A (p.Gly71Arg, at the coding region of the gene)[22]. The study of Alsarhan et al[3] did not address this regional variation.

CONCLUSION

The study of Alsarhan et al[3] demonstrates that in populations with a high prevalence of hereditary diseases, genetic testing can facilitate clinical diagnosis and the development of precision treatment plans. The findings also suggest that gene mutation type is correlated with disease severity. However, the underlying pathogenic mechanisms of the identified NR1I3 genetic variant in pediatric GI diseases warrant further research. Overall, the study of Alsarhan et al[3] reveals that precision pediatric medicine need not be limited to traditional symptom management when targeted, genotype-specific care is adopted.