Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS; MIM #122470, 300590, 610759, 614701, 300882) is a rare and clinically variable disorder that affects multiple organs. It is characterized by intellectual disability (mild to severe), distinctive facial features, prenatal and postnatal growth retardation, and hirsutism. Congenital anomalies include malformations of the upper limbs, gastrointestinal malformation/rotation, pyloric stenosis, diaphragmatic hernia, heart defects and genitourinary malformations. Gastroesophageal reflux disease is present in almost all patients. In addition to classic forms, milder phenotypes have been reported. To date five genes [NIPBL (Nipped-B-like protein), SMC1A (structural maintenance of chromosomes 1A), SMC3 (structural maintenance of chromosomes 3), RAD21 (human homolog of Schizosaccharomyces pombe radiation sensitive mutant 21) and HDAC8 (histone deacetylase 8)] have been associated with CdLS and mutations of these genes comprise the underlying defect in 70% of the patients. Here, we will provide a brief review of the clinical features of CdLS, summarize the known underlying genetic defects, prenatal and postnatal diagnosis possibilities, and genetic counseling.

Boyle MI ，Jespersgaard C ，Brøndum-Nielsen K ，Bisgaard AM ，Tümer Z ... -  《-》

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 ... -  《-》

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach.

Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS therapeutic approaches.

Sarogni P ，Pallotta MM ，Musio A 《-》

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 ... -  《-》