Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features

30. Januar, 2024

Morad Ansari 1, Kamli N W Faour 2, Akiko Shimamura 3, Graeme Grimes 4, Emeline M Kao 5, Erica R Denhoff 5, Ana Blatnik 6, Daniel Ben-Isvy 7, Lily Wang 7, Benjamin M Helm 8, Helen Firth 9, Amy M Breman 8, Emilia K Bijlsma 10, Aiko Iwata-Otsubo 8, Thomy J L de Ravel 11, Vincent Fusaro 12, Alan Fryer 13, Keith Nykamp 12, Lara G Stühn 14, Tobias B Haack 14, G Christoph Korenke 15, Panayiotis Constantinou 16, Kinga M Bujakowska 17, Karen J Low 18, Emily Place 17, Jennifer Humberson 19, Melanie P Napier 20, Jessica Hoffman 20, Jane Juusola 20, Matthew A Deardorff 21, Wanqing Shao 22, Shira Rockowitz 23, Ian Krantz 24, Maninder Kaur 24, Sarah Raible 24, Victoria Dortenzio 24, Sabine Kliesch 25, Moriel Singer-Berk 26, Emily Groopman 27, Stephanie DiTroia 26, Sonia Ballal 28, Siddharth Srivastava 29, Kathrin Rothfelder 30, Saskia Biskup 31, Jessica Rzasa 32, Jennifer Kerkhof 32, Haley McConkey 32, Bekim Sadikovic 32, Sarah Hilton 33, Siddharth Banka 34, Frank Tüttelmann 35, Donald Conrad 36, Anne O’Donnell-Luria 37, Michael E Talkowski 38, David R FitzPatrick 4, Philip M Boone 39


Heterozygous missense variants and in-frame indels in SMC3 are 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 with SMC3 loss-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 in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves 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 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF 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.

Keywords: CdLS3; Cornelia de Lange syndrome; LoF; SMC3; cohesin; loss-of-function.

Update of: PMID: 37808847