SMC1A – Cornelia de Lange syndrome

SMC1A encodes a core cohesin subunit on the X chromosome. Heterozygous mutations in SMC1A cause an X-linked form of Cornelia de Lange syndrome (CdLS), characterized by variable facial dysmorphism, growth delay, and cognitive impairment. Initial screening of 11 CdLS boys without NIPBL anomalies identified two de novo missense SMC1A mutations and established SMC1A as a significant contributor to X-linked CdLS (PMID:17221863).

Inheritance is X-linked dominant, with both de novo and familial transmission. To date, 26 distinct SMC1A variants—including missense and in-frame deletions that preserve the reading frame—have been reported in ~70 affected individuals (PMID:22140011). Familial segregation across three generations was observed for the novel c.3178G>A (p.Glu1060Lys) variant, confirming pathogenicity in a mild CdLS pedigree (PMID:26354354).

The variant spectrum is dominated by in-frame changes and missense substitutions clustering in the hinge and ATPase head domains. A recurrent missense allele, c.1487G>A (p.Arg496His), impairs the cellular response to genotoxic stress, indicating a dominant-negative mechanism (PMID:22140011).

Functional studies demonstrate that mutant SMC1A proteins retain cohesin ring assembly but alter chromatin binding dynamics, leading to transcriptional dysregulation. Global transcriptome profiling in HDAC8- and NIPBL-mutant CdLS cell lines indicates common downstream pathways, supporting a dominant-negative effect of SMC1A variants on cohesin-mediated gene regulation (PMID:25574841).

Somatic mosaicism and variable X-chromosome inactivation contribute to phenotypic heterogeneity, with mosaic deletions detected in buccal cells but absent in blood in mild cases. Truncating SMC1A variants define a severe developmental and epileptic encephalopathy distinct from classic CdLS, expanding the phenotypic spectrum (PMID:28102598).

Integration of genetic and functional data establishes a definitive SMC1A–CdLS association. SMC1A screening is recommended in CdLS gene panels and in females with early-onset cluster seizures lacking classical CdLS features.

References

• Human Mutation • 2007 • Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations. PMID:17221863
• American journal of medical genetics. Part A • 2012 • SMC1A codon 496 mutations affect the cellular response to genotoxic treatments. PMID:22140011
• American journal of medical genetics. Part A • 2017 • Novel findings of left ventricular non-compaction cardiomyopathy, microform cleft lip and poor vision in patient with SMC1A-associated Cornelia de Lange syndrome. PMID:28102598
• The Journal of clinical investigation • 2015 • Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. PMID:25574841

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