Biallelic variants of the first Kunitz domain of SPINT2 cause none syndromic form of congenital diarrhea and tufting enteropathy

Abstract Biallelic SPINT2 pathogenic variants cause a syndromic form of congenital diarrhea and enteropathy (OMIM 270420). To date, all 34 patients reported presented with additional extra-intestinal syndromic features. We report on a 5-year-old girl who presented early in life with congenital diarrhea and was found to have a novel homozygous variant in SPINT2. She presented with congenital diarrhea, pathological studies confirmed tufting enteropathy, and at the age of 5 years, she did not develop any extra-intestinal syndromic features. The variant (NM_021102.4: c.203A > G (p. [Tyr68Cys]) detected in homozygosity status is the first missense mutation reported in the 1st Kunitz domain (KD1) of SPINT2 in humans. Previously in-vitro functional studies of this variant confirmed the deleterious effect leading to complete loss of inhibitory activity of the intestinal serine proteases. Furthermore, this is the first description of SPINT2-related diarrhea in a patient who lived without the need for long-term total parenteral nutrition. This study expands the clinical and molecular characteristics of SPINT-related conditions.