Agnathia-otocephaly is a rare craniofacial malformation complex that is caused by de novo heterozygous and biallelic mutations in PRRX1 in two unrelated babies, respectively. We studied the PRRX1 gene in a non-consanguineous Indonesian female infant who was diagnosed prenatally with severe retrognathia (bilateral Pruzansky type III). Her older affected brother died shortly after birth and had agnathia-otocephaly. A c.266_269dupAAAA frameshift mutation in the poly A tract in PRRX1 was identified in the proband while her father only had an inframe duplication (c.267_269dupAAA) of the adenosine trinucleotide residue. Expression of both mutations in COS7 cells showed loss of function of the frame shift mutation only. Results of SNP genotyping coupled with recurrence of this novel mutation in this family are consistent with a paternally derived germline mosaicism rather than autosomal recessive inheritance as predicted by the family history. Severe retrognathia (bilateral Pruzansky III) and agnathia-otocephaly represent a spectrum of craniofacial malformations in this family.
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