Overlap of genetic factors among craniosynostosis and autism spectrum disorder: the presence of autistic cases without craniosynostosis in carriers of shared variants.

Objective: A significant overlap of the risk genes respectively listed for craniosynostosis and autism was recently demonstrated in each case series. The purposes of this article were to review the clinical manifestations systemically in previously reported individual cases with the shared variants and to confirm the pleiotropic associations between genotype and phenotype.

Methods: The risk genes or loci were retrieved from the PubMed database (last searched March 2024) as genetic factors for which genotype-phenotype associations were reported in at least 2 different individuals. Clinical details were reviewed in cases with shared genetic factors between craniosynostosis and autism spectrum disorder. In the genotype-phenotype association of syndromic craniosynostosis genes, both syndromic involvement of autistic traits and nonsyndromic autism cases with nonsyndromic variants in the flanking regions of the syndromic mutations were included.

Results: Nonsyndromic craniosynostosis and autism are both underpinned by complex polygenic networks that include multiple risk genes or loci, and a considerable part of the networks might overlap. Although nonsyndromic mild trigonocephaly and autism might be closely associated in carriers of the shared variants, the presence of cases with autism without mild trigonocephaly was confirmed in a PJA1 variant case. As one of the characteristics of epistasis, ethnic specificity has been demonstrated in the interactions between SMAD6 and BMP2 variants. The presence of autism cases without craniosynostosis on a shared genetic basis was also confirmed in syndromic craniosynostosis risk genes and loci, suggesting that the causal relationship from craniosynostosis to autism is unnecessary for the development of autism spectrum disorder.

Conclusions: Regarding the 3 possibilities of the association between craniosynostosis and neurodevelopmental comorbidities proposed by Kapp-Simon's group, only the independent pathway theory can explain the genotype-phenotype findings. There is no causal relationship between craniosynostosis and autism spectrum disorder in the independent pathway theory. Because the mechanical hindrance of brain expansion from poor compliance of the affected cranial vault is less likely in mild craniosynostosis cases, surgical indication of cranioplasty for mild trigonocephaly should never be confused with that of overt craniosynostosis. If there is no cosmetic indication for the metopic ridge in mild trigonocephaly cases with developmental comorbidities, there is no reason for surgical intervention.