MED12 – Hardikar Syndrome

Hardikar syndrome (HS; MONDO:0012997) is a female-specific, X-linked dominant multiple congenital anomaly syndrome characterized by cholestatic liver disease, pigmentary retinopathy, orofacial clefting and other malformations. De novo heterozygous loss-of-function variants in MED12 (HGNC:11957) were first implicated in HS by exome sequencing of seven unrelated females, all demonstrating skewed X-chromosome inactivation and concordant phenotypes (PMID:33244166).

Patients present with facial clefting (orofacial cleft; HP:0000202), pigmentary retinopathy (HP:0000580), intestinal malrotation (HP:0002566) and biliary anomalies leading to cholestasis. Multi-centre case series now include 23 probands (all de novo; X-linked dominant; 0 familial segregation) with consistent hepatic, ocular and craniofacial findings (PMID:33244166; PMID:35385210; PMID:39045790). Prenatal reports describe fetuses with diaphragmatic hernia, omphalocele and cleft palate carrying frameshift variants such as c.5500_5507del (p.Gln1184ArgfsTer14) (PMID:38777622) and whole-gene deletions (PMID:39702865).

The MED12 variant spectrum in HS comprises 15+ distinct de novo events: nonsense, frameshift and splice-site mutations distributed throughout the coding region, and large Xq13.1 deletions overlapping MED12. A representative pathogenic allele is c.5500_5507del (p.Gln1184ArgfsTer14) (de novo) identified in a fetus with cleft palate and cardiac defects (PMID:38777622).

Functional studies demonstrate that MED12 haploinsufficiency disrupts primary cilia formation and attenuates hedgehog and YAP signaling pathways in patient-derived cells, correlating with craniofacial and biliary dysgenesis seen in HS (PMID:39045790). These data support a loss-of-function mechanism rather than dominant-negative activity.

No studies to date refute the association or report healthy carriers of MED12 LoF variants with HS features. The consistency of de novo MED12 mutations, lack of alternative genetic explanations, and concordant cellular phenotypes underscore a robust gene-disease link.

In summary, de novo heterozygous LoF variants in MED12 cause Hardikar syndrome via haploinsufficiency. Genetic testing for MED12 variants in females with pigmentary retinopathy, clefting and cholestasis is clinically indicated and informs prognosis and management.

References

• Genetics in Medicine • 2021 • De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females PMID:33244166
• American Journal of Medical Genetics Part A • 2022 • MED12-related Hardikar syndrome: Two additional cases and novel phenotypic features PMID:35385210
• Genetics in Medicine • 2024 • Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome PMID:39045790
• Retinal Cases & Brief Reports • 2024 • Multimodal retinal imaging findings in Hardikar syndrome PMID:37603453
• Prenatal Diagnosis • 2024 • A novel MED12 pathogenic variant in a female fetus with facial cleft and cardiac defects identified in the first trimester PMID:38777622
• Prenatal Diagnosis • 2025 • A whole MED12 gene deletion in a female fetus with features encountered in Hardikar syndrome PMID:39702865

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