De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes.

Gil-Rodríguez MC ，Deardorff MA ，Ansari M ，Tan CA ，Parenti I ，Baquero-Montoya C ，Ousager LB ，Puisac B ，Hernández-Marcos M ，Teresa-Rodrigo ME ，Marcos-Alcalde I ，Wesselink JJ ，Lusa-Bernal S ，Bijlsma EK ，Braunholz D ，Bueno-Martinez I ，Clark D ，Cooper NS ，Curry CJ ，Fisher R ，Fryer A ，Ganesh J ，Gervasini C ，Gillessen-Kaesbach G ，Guo Y ，Hakonarson H ，Hopkin RJ ，Kaur M ，Keating BJ ，Kibaek M ，Kinning E ，Kleefstra T ，Kline AD ，Kuchinskaya E ，Larizza L ，Li YR ，Liu X ，Mariani M ，Picker JD ，Pié Á ，Pozojevic J ，Queralt E ，Richer J ，Roeder E ，Sinha A ，Scott RH ，So J ，Wusik KA ，Wilson L ，Zhang J ，Gómez-Puertas P ，Casale CH ，Ström L ，Selicorni A ，Ramos FJ ，Jackson LG ，Krantz ID ，Das S ，Hennekam RC ，Kaiser FJ ，FitzPatrick DR ，Pié J ... -  《-》

Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype.

Mannini L ，Cucco F ，Quarantotti V ，Krantz ID ，Musio A ... -  《-》

Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) manifests facial dysmorphic features, growth and cognitive impairment, and limb malformations. Mutations in three genes (NIPBL, SMC1A, and SMC3) of the cohesin complex and its regulators have been found in affected patients. Here, we present clinical and molecular characterization of 30 unrelated patients with CdLS. Eleven patients had mutations in NIPBL (37%) and three patients had mutations in SMC1A (10%), giving an overall rate of mutations of 47%. Several patients shared the same mutation in NIPBL (p.R827GfsX2) but had variable phenotypes, indicating the influence of modifiers in CdLS. Patients with NIPBL mutations had a more severe phenotype than those with mutations in SMC1A or those without identified mutations. However, a high incidence of palate defects was noted in patients with SMC1A mutations. In addition, we observed a similar phenotype in both male and female patients with SMC1A mutations. Finally, we report the first patient with an SMC1A mutation and the Sandifer complex.

Pié J ，Gil-Rodríguez MC ，Ciero M ，López-Viñas E ，Ribate MP ，Arnedo M ，Deardorff MA ，Puisac B ，Legarreta J ，de Karam JC ，Rubio E ，Bueno I ，Baldellou A ，Calvo MT ，Casals N ，Olivares JL ，Losada A ，Hegardt FG ，Krantz ID ，Gómez-Puertas P ，Ramos FJ ... -  《-》

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.

Yuan B ，Pehlivan D ，Karaca E ，Patel N ，Charng WL ，Gambin T ，Gonzaga-Jauregui C ，Sutton VR ，Yesil G ，Bozdogan ST ，Tos T ，Koparir A ，Koparir E ，Beck CR ，Gu S ，Aslan H ，Yuregir OO ，Al Rubeaan K ，Alnaqeb D ，Alshammari MJ ，Bayram Y ，Atik MM ，Aydin H ，Geckinli BB ，Seven M ，Ulucan H ，Fenercioglu E ，Ozen M ，Jhangiani S ，Muzny DM ，Boerwinkle E ，Tuysuz B ，Alkuraya FS ，Gibbs RA ，Lupski JR ... -  《-》

Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation.

Deardorff MA ，Kaur M ，Yaeger D ，Rampuria A ，Korolev S ，Pie J ，Gil-Rodríguez C ，Arnedo M ，Loeys B ，Kline AD ，Wilson M ，Lillquist K ，Siu V ，Ramos FJ ，Musio A ，Jackson LS ，Dorsett D ，Krantz ID ... -  《-》