We identified three novel PV in PITX2 (NM_153427.2:c.217G>A, c.233T>C and c.279del) and two in FOXC1 [NM_001453.2:c.274C>T (novel) and c.454T>A] in five ARS patients.
Here, we investigated the effect of four ARS missense variants on FOXC1 structure and function, and examined the predictive value of four in silico programs for all 31 FOXC1 missense variants identified to date.
Intragenic mutations in the homeobox gene PITX2 or the transcription factor encoding FOXC1 were identified, and genomic rearrangements encompassing either gene also cause ARS.
We suggest that this FOXC1 mutation causes typical ARS, and that our results may be useful for better understanding of the spectrum of FOXC1 mutations and the role of FOXC1 in the development and progression of ARS.
In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects.
A novel mutation in Helix1 and a novel deletion in Wing1 and Beta2 of the forkhead domain of the FOXC1 gene have been identified in two families with ARS.
Direct sequencing of FKHL7 detected a C67T mutation that segregated with the ARS phenotype in this family, but was not detected in over 80 control chromosomes.