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

28. September , 2023

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


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 13 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 a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links to SMC3 including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest that SMC3 pLoF variants reduce SMC3 expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature of SMC3 loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance 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.