Identification of a novel candidate locus at 21q22.3 for isolated intestinal Malrotation

Intestinal malrotation (IM) is a relatively common congenital anomaly of the gastrointestinal tract resulting from abnormal rotation during embryonic development. While some cases of IM are part of syndromic manifestations, most are isolated, with their genetic basis remaining largely unknown. We present a familial case of apparently autosomal recessive isolated IM in a consanguineous kindred of Arab-Bedouin descent. Nine individuals from two nuclear families were recruited. Homozygosity mapping and logarithm of odds (LOD) score calculations were performed using single nucleotide polymorphism (SNP) array data. Whole-exome and whole-genome sequencing data were analyzed to identify candidate variants. Various analysis and interpretation tools were applied to evaluate and describe potential disease-associated variants. Homozygosity mapping identified a 2 Mb candidate locus on chromosome 21q22.3. Multipoint linkage analysis identified an overlapping locus on chromosome 21 (maximal LOD score: 3.168). A missense variant in PCNT (Gln1951Pro), along with several other segregating candidates, was evaluated. Our findings demonstrate a novel candidate locus at chromosome 21q22.3 associated with isolated IM, with PCNT emerging as a potential candidate gene. Further studies involving additional affected families and functional validation are required to establish the contribution of this locus and the identified variant to the pathogenesis of isolated IM.