Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

Abstract

AbstractHeterozygous missense variants and in-frame indels inSMC3are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated withSMC3loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants inSMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show thatSMC3behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 13 individuals withSMC3pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism reminiscent of atypical CdLS. Comparisons to individuals withSMC3missense/in-frame indel variants demonstrated a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants inSMC3were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links toSMC3including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest thatSMC3pLoF variants reduceSMC3expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature ofSMC3loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance in subjects withSMC3pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multi-layered genomic data paired with careful phenotyping.