Mandibular-pelvic-patellar syndrome is a novelPITX1-related disorder due to alteration of PITX1 transactivation ability

PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. TwoPITX1-related human disorders have been reported to date:PITX1ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a ``lower limb'' appearance;PITX1deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novelPITX1missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with thePitx1-/- mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused byTBX4haploinsufficiency, and with the phenotypic spectrum caused bySOX9anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum ofPITX1-related disorders and suggest a common pattern of developmental abnormalities in disorders of thePITX1-TBX4-SOX9signaling pathway.