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The paired-related homeobox 1 gene (PRRX1) encodes a homeodomain transcription factor essential for mesenchymal differentiation and cranial suture maintenance. Murine Prrx1 is expressed in preosteogenic cells of cranial sutures, highlighting its developmental importance.
A trio-based sequencing study screened heterozygous missense and loss-of-function (LoF) variants in PRRX1 among 1,458 patients with craniosynostosis. Genome sequencing identified 2 of 9 sporadic syndromic/multisuture cases and exome or targeted sequencing detected 9 of 1,449 additional patients with rare homeodomain alterations (PMID:37154149). Collaborative ascertainment added 7 more affected individuals across 4 families with putatively pathogenic PRRX1 variants (PMID:37154149).
In total, 18 probands from 15 unrelated kindreds carried heterozygous PRRX1 variants, predominantly splice-site and missense changes within the homeodomain, including c.418-1G>A. Segregation in 7 additional affected relatives and inheritance from unaffected carriers indicate autosomal dominant transmission with incomplete penetrance (estimated 12.5%) (PMID:37154149).
Clinically, bicoronal or other multisuture synostosis occurred in 11 of 17 evaluable cases (65%), with variable syndromic manifestations. No recurrent or founder alleles were noted, reflecting allelic heterogeneity. Carrier frequency data are not available.
Functional immunofluorescence assays revealed that homeodomain missense variants mislocalize PRRX1 protein, abolishing nuclear localization consistent with haploinsufficiency (PMID:37154149). Concordant murine expression data further support dosage sensitivity in suture development.
Integration of genetic and experimental evidence establishes haploinsufficiency of PRRX1 as a cause of autosomal dominant craniosynostosis with reduced penetrance. Further studies should refine prevalence and penetrance estimates.
Key Take-home: PRRX1 heterozygous disruptive variants cause craniosynostosis via autosomal dominant haploinsufficiency with incomplete penetrance, informing genetic diagnosis and counseling.
Gene–Disease AssociationStrong18 probands across 15 unrelated kindreds, 4 familial segregations, concordant functional data Genetic EvidenceStrong18 probands with heterozygous PRRX1 variants in homeodomain, including 4 multi-generation families, reaching genetic evidence cap Functional EvidenceModerateImmunofluorescence shows mislocalization of homeodomain variants; murine expression supports developmental role |