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

Ansari, Morad; Faour, Kamli N.W.; Shimamura, Akiko; Grimes, Graeme; Kao, Emeline M.; Denhoff, Erica R.; Blatnik, Ana; Ben-Isvy, Daniel; Wang, Lily; Helm, Benjamin M.; Firth, Helen; Breman, Amy M.; Bijlsma, Emilia K.; Iwata-Otsubo, Aiko; de Ravel, Thomy J.L.; Fusaro, Vincent; Fryer, Alan; Nykamp, Keith; Stühn, Lara G.; Haack, Tobias B.; Korenke, G. Christoph; Constantinou, Panayiotis; Bujakowska, Kinga M.; Low, Karen J.; Place, Emily; Humberson, Jennifer; Napier, Melanie P.; Hoffman, Jessica; Juusola, Jane; Deardorff, Matthew A.; Shao, Wanqing; Rockowitz, Shira; Krantz, Ian; Kaur, Maninder; Raible, Sarah; Dortenzio, Victoria; Kliesch, Sabine; Singer-Berk, Moriel; Groopman, Emily; DiTroia, Stephanie; Ballal, Sonia; Srivastava, Siddharth; Rothfelder, Kathrin; Biskup, Saskia; Rzasa, Jessica; Kerkhof, Jennifer; McConkey, Haley; Sadikovic, Bekim; Hilton, Sarah; Banka, Siddharth; Tüttelmann, Frank; Conrad, Donald F.; O’Donnell-Luria, Anne; Talkowski, Michael E.; FitzPatrick, David R.; Boone, Philip M.

doi:10.1016/j.xhgg.2024.100273

Cited by 1 publication

(1 citation statement)

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“…Two of the previously reported cases of CdLS3 were caused by mutations located in exon 22 of the SMC3 (c.2494_2499del, c.2515C>T), with clinical severity ranging from moderate to severe (Gil-Rodríguez et al, 2015). Ansari et al demonstrate that individuals with heterozygous, predicted loss-offunction variants in SMC3 are survivable, and phenotypes associated with variable developmental delay, growth deficiency, and/or facial dysmorphism, that are milder than but overlapping with that of SMC3 missense/in-frame indel variants present in CdLS cohorts (Ansari et al, 2024). Therefore, we strongly suspect that this variant (c.2535+1G>A) in vivo is the cause of most of the findings in P1.…”

Section: Discussionmentioning

confidence: 99%

Identification of two novel heterozygous variants of SMC3 with Cornelia de Lange syndrome

Lei,

Song,

Zheng

et al. 2024

Molec Gen & Gen Med

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BackgroundCornelia de Lange syndrome (CdLS) is a multisystem genetic disorder, and cases caused by variants in the structural maintenance of chromosomes protein 3 (SMC3) gene are uncommon. Here, we report two cases of CdLS associated with novel pathogenic variants in SMC3 from two Chinese families.MethodsClinical presentations of two patients with CdLS were evaluated, and specimens from the patients and other family members were collected for Trio‐based whole‐exome sequencing. Pyrosequencing, chip‐based digital PCR, minigene splicing assay, and in silico analysis were carried out to elucidate the impact of novel variants.ResultsNovel heterozygous variants in SMC3 were identified in each proband. One harbored a novel splicing and mosaic variant (c.2535+1G>A) in SMC3. The mutated allele G>A conversion was approximately 23.1% by digital PCR, which indicated that 46.2% of peripheral blood cells had this variant. Additionally, in vitro minigene splicing analysis validated that the c.2535+1G>A variant led to an exon skipping in messenger RNA splicing. The other carried a heterozygous variant (c.435C>A), which was predicted to be pathogenic as well as significantly altered in local electrical potential. The former showed multiple abnormalities and marked clinical severity, and the latter mainly exhibited a speech developmental disorder and slightly facial anomalies.ConclusionBoth patients were clinically diagnosed with Cornelia de Lange syndrome 3 (CdLS3). The newly identified SMC3 gene variants can expand the understanding of CdLS3 and provide reliable evidence for genetic counseling to the affected family.

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Section: Discussionmentioning

confidence: 99%