The genetic landscape of congenital diarrheas and very early onset inflammatory bowel disease in the Middle East

Objectives Monogenic causes of congenital diarrheas and enteropathies (CoDE) and very early onset inflammatory bowel disease (VEOIBD) are mostly recessive and therefore more prevalent in populations with increased consanguinity rates. To assess the genetic basis of these disorders in a likely high‐prevalence population, we established a multi‐center cohort of patients across the Middle East. Methods Patients were enrolled across four centers in the Middle East. Clinical data, including self‐reported consanguinity, were collected. Trio whole exome sequencing (WES) was performed, and genomic data were processed through a standardized variant identification pipeline. Patients who inherited a rare variant consistent with the disease in a gene known to be causative for CoDE or VEOIBD were classified as having a monogenic etiology. Self‐reported consanguinity and homozygosity mapping were analyzed and correlated with monogenic diagnoses. Results WES from trios of 27 patients (13 CoDE and 14 VEOIBD) were analyzed. Higher frequency of consanguinity was self‐reported by the CoDE families (11/13, 84.6%) and confirmed by homozygosity mapping than in the VEOIBD group (4/14, 28.6%). A monogenic cause of disease was identified in 10 of 13 CoDE patients (76.9%) in the following genes: EPCAM , SPINT2 , DGAT1, MYO5B, SPINT2 , and STXBP2 . A single VEOIBD patient (7.1%) had an identifiable monogenic cause of disease in SKIV2L . Conclusions Within this limited cohort, the diagnostic yield for known genes associated with CoDE was high, consistent with the primarily monogenic etiology and high consanguinity. For VEOIBD, the diagnostic yield was lower and similar to that reported in North America.