A Novel ANO1 Gene Variant is Associated with Intestinal Dysmotility Syndrome Masquerading as Hirschsprung Disease: A Case Report

Abstract

Anoctamin 1 (ANO1)-related intestinal dysmotility syndrome (OMIM: 620045) is an extremely rare disorder with only 2 cases reported in the medical literature. We present the clinical scenario of a 2-month-old male infant that presented to our center with diarrhea, vomiting, and abdominal distension. Routine investigations did not yield a clear diagnosis. Whole-exome sequencing showed a novel homozygous nonsense ANO1 pathogenic variant (c.1273G>T) with a protein alternation of p.Glu425Ter that fits the patient’s phenotype. Sanger sequencing revealed the same ANO1 variant in both parents in a heterozygous form confirming an autosomal recessive mode of inheritance. The patient experienced multiple bouts of diarrhea-related metabolic acidosis, dehydration, and severe electrolyte imbalances that required intensive care unit monitoring. The patient was managed conservatively and being followed regularly in an outpatient setting.

Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

“…The broad spectrum of tissue expression explains the wide range of disorders associated with their respective disrupted function. Several ANO family members have been associated with a variety of human diseases or increased risks for diseases such as intestinal dysmotility (MIM: 620045 ) 31 , 32 and moyamoya disease (MIM: 620687 ) 33 with ANO1 , dystonia (MIM: 615034 ) 34 , 35 with ANO3 , gnathodiaphyseal dysplasia (MIM: 166260 ) 36 , 37 , 38 , 39 and muscular dystrophies (MIM: 613319 , 611307 ) 40 , 41 , 42 , 43 , 44 with ANO5 , disturbed blood coagulation (Scott syndrome, MIM 262890 ) 24 , 45 with ANO6 , spinocerebellar ataxia (MIM: 613728 ) 46 , 47 , 48 with ANO10 , and pancreatic and colorectal cancer 49 , 50 with ANO9 . ANO4 has not been linked to a Mendelian phenotype so far, but genome-wide association studies showed an association between single-nucleotide polymorphisms near ANO4 and various neurological diseases, such as schizophrenia, Alzheimer disease, and anxiety disorder.…”

“… 57 Furthermore, ANO4 was found upregulated in human tumor samples compared to normal kidney tissue, suggesting a potential role as a prognostic biomarker in non-metastasized clear cell renal cell carcinoma. 31 …”