Heterozygous loss-of-function SMC3 variants are associated with variable and incompletely penetrant growth and...

Area of Science:

• Genetics
• Developmental Biology
• Human Genetics

Background:

• Heterozygous missense variants in SMC3 cause Cornelia de Lange syndrome (CdLS) via a dominant-negative mechanism.
• The phenotypic spectrum of SMC3 loss-of-function (LoF) variants was previously uncharacterized, prompting investigation into potential alternative phenotypes or lethality.

Approach:

• Identified individuals with heterozygous predicted LoF (pLoF) variants in SMC3 using matchmaking servers and patient registries.
• Analyzed population databases to assess mutational intolerance in the SMC3 gene.
• Characterized phenotypes in individuals with SMC3 pLoF variants and compared them to those with missense/indel variants.

Key Points:

• SMC3 is a highly constrained gene, intolerant to pLoF variants, behaving as an archetypal haploinsufficient gene.
• SMC3 pLoF variants are associated with variable developmental phenotypes including low growth, developmental delay, intellectual disability, and dysmorphism, often milder than typical CdLS.
• Nonpenetrance was observed in some carriers, with some exhibiting distinct conditions like bone marrow failure or acute myeloid leukemia.

Conclusions:

• SMC3 pLoF variants expand the spectrum of cohesinopathies, revealing a complex allelic architecture with variable penetrance.
• Transcriptomic and epigenetic analyses indicate reduced SMC3 expression but not a distinct CdLS methylation signature.
• This study highlights the importance of multi-layered genomic data and phenotyping for identifying disease-associated LoF-constrained genes.