Genetic Insights into Pediatric Achalasia Cardia: A Pilot Study on Family Pedigrees and Risk Assessment in Highly Consanguineous and Closely Related Populations

Background: Congenital achalasia cardia, a rare esophageal motility disorder, presents with dysphagia and progressive esophageal dysfunction. The interplay of genetic predispositions and familial structures remains underexplored, particularly in high-consanguinity populations. This study aimed to elucidate congenital achalasia's genetic underpinnings and inheritance patterns through a detailed analysis of 15 pediatric cases from consanguineous families in a localized region.

Methods: A cohort of 15 pediatric patients diagnosed with congenital achalasia cardia was identified within a local population known for high rates of consanguinity (15 families with at least one member diagnosed with congenital achalasia cardia were included) living in the same town, and they all belong to one clan. Confirmed diagnosis of congenital achalasia cardia through clinical and diagnostic workup. Genetic investigations included whole-genome sequencing (WGS) and targeted KIT, RET, ANO1, and SCN5A analysis. The KIT and RET mutation frequency was compared between affected and non-affected members using a chi-squared test (P < 0.001). Differences in neural crest cell migration and protein expression were analyzed using unpaired t-tests (P = 0.05). Logarithm of the odds (LOD) score was calculated for linkage in affected families. Pedigree charts were constructed using specialized software, highlighting generational patterns and relationships.

Results: High consanguinity rates (80%) and familial clustering underscored autosomal recessive inheritance. KIT and RET mutations were identified in 60% of cases, with combined mutations linked to severe phenotypes. ANO1 and SCN5A polymorphisms were detected in 40% of cases, contributing to functional impairments in smooth muscle contraction and neural signaling. Early intervention led to significant clinical improvement in 80% of cases, while delayed diagnosis correlated with severe complications. A LOD score >4.0 validated the genetic linkage of identified mutations.

Conclusion: This study highlights the genetic complexity of congenital achalasia, emphasizing the dual role of neural and muscular defects. Findings advocate for systematic genetic screening, early intervention, and genetic counseling to mitigate disease burden in high-risk populations. Future research should expand on these findings to inform precision medicine strategies and public health interventions.