Postzygotic mosaicism in SMC1A and the first reported case of a female with Cornelia de Lange syndrome.

Postzygotic mosaicism (PZM) has been increasingly recognized in Cornelia de Lange syndrome (CdLS). However, it has been scarcely described when the genetic cause resides in SMC1A, an X-linked cohesin member implicated in approximately 5% of cases. Here, we report the first female patient with classic CdLS harboring a PZM variant in SMC1A and provide a comprehensive characterization of mosaicism in this gene. The identified PZM variant [SMC1A:NM_006306.3:c.2369 = /G > A; p.(Arg790Gln)], was detected in blood and buccal swab-derived DNA at around 30% allele frequency. Molecular dynamics simulations suggest that this mutation disrupts the elbow domain of SMC1A, potentially impairing cohesin function. Further delineation of phenotypes and genotypes associated with PZM variants in SMC1A reveals that, similar to constitutive variants, mosaic mutations are predominantly missense and distributed throughout the gene. Moreover, the phenotype of patients carrying mosaic variants is clinically indistinguishable from those with constitutive mutations, and purifying selection of the pathogenic variant in blood is suggested, as previously observed in NIPBL-related CdLS. However, this process may be more complex in SMC1A due to its X-linked nature. Our findings underscore the importance of high-sensitivity sequencing techniques for detecting mosaicism and highlight the complexity of X-linked mosaic variants in disease expressivity. Further functional studies and larger cohorts are crucial to improve genotype-phenotype correlations and diagnostics in CdLS.