A Novel Intronic Variant in MED12 Associated with a Predominantly Hepatobiliary Phenotype Suggestive of Hardikar Syndrome: A Case Report and Literature Review

Background/Objectives: Hardikar syndrome (HDKR) is an X-linked dominant disorder caused by pathogenic variants in the Mediator complex subunit 12 (MED12) gene, predominantly affecting females. It is characterized by multisystem congenital anomalies involving the foregut, biliary tract, craniofacial structures, eyes, skeleton, and genitourinary system, with generally preserved neurodevelopment. Only 34 cases have been reported to date, and most exhibit multiple congenital anomalies. We describe a female infant who presented with progressive cholestatic liver disease and complex hepatobiliary malformations, including an absent gallbladder and paucity of bile ducts, with unremarkable prenatal imaging. The clinical course was notable for hepatosplenomegaly, markedly elevated total bile acids, portal hypertension with esophageal varices, and eventual liver failure. Methods: Whole-exome sequencing (WES) was performed to investigate the underlying genetic etiology, followed by parental segregation analysis using Sanger sequencing to confirm and characterize the identified variant. Results: WES identified a novel de novo intronic heterozygous variant in MED12 (c.3868-5C>G). Unlike most previously reported cases, the predominant and early manifestation in our case was severe hepatobiliary disease with limited additional anomalies, suggesting possible phenotypic variability within the MED12-related Hardikar syndrome spectrum. The identified MED12 variant is classified as a variant of uncertain significance (VUS). Conclusions: This case underscores the diagnostic utility of WES in infants with unexplained cholestasis, highlights the importance of considering noncoding variants, and illustrates the value of reporting well-characterized patients carrying novel VUS, thereby contributing to the growing body of clinical and molecular evidence on MED12-related Hardikar syndrome.