A Chinese Case of Cornelia de Lange Syndrome Caused by a Pathogenic Variant in SMC3 and a Literature Review.

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder, and cases caused by variants in SMC3 are infrequent. This article describes a case of CdLS related to a pathogenic variant in SMC3 and performs a literature review. We collected clinical data and biological samples from a 12-year-old boy with "short stature for 11 years". Gene variants in the proband were detected by whole-exome sequencing, and the variants in his parents were verified by Sanger sequencing. All SMC3-related CdLS patients from the PubMed and Web of Science databases were collected and summarized using the available data. A pathogenic variant in SMC3 in the proband, c.1942A>G, was identified. Neither of his parents carried the same variant. Twenty-eight patients were diagnosed with CdLS with variants in SMC3, including the cases in this study and those reported in the literature, where half of the variant types were missense, followed by 32% (9/28) with a deletion and 11% (3/28) with a duplication. All patients showed symptoms of verbal development delay and intellectual disability to different degrees, and 90% patients had long eyelashes while 89% patients had arched eyebrows. This study summarized different gene variants in SMC3 and the frequencies of the various clinical manifestations according to the reported literature. For CdLS caused by SMC3 variants, short stature and facial dysmorphic features are the two most important clinical clues. Definite diagnosis of this rare disease may be challenging clinically; thus, it is significant to use molecular diagnosis.

Li R ，Tian B ，Liang H ，Chen M ，Yang H ，Wang L ，Pan H ，Zhu H ... -  《Frontiers in Endocrinology》

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

Cornelia 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. Clinical 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. Novel 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. Both 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.

Lei Z ，Song X ，Zheng X ，Wang Y ，Wang Y ，Wu Z ，Fan T ，Dong S ，Cao H ，Zhao Y ，Xia Z ，Gao L ，Shang Q ，Mei S ... -  《Molecular Genetics & Genomic Medicine》

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 ... -  《-》

Analysis of clinical and genetic characteristics in 10 Chinese individuals with Cornelia de Lange syndrome and literature review.

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with variable multisystem involvement and genetic heterogeneity. We aimed to analyze the clinical and genetic characteristics of Chinese individuals with CdLS. We collected data regarding the neonatal period, maternal status, clinical manifestation, including facial dimorphisms and development, and follow-up treatment for individuals diagnosed with CdLS. In individuals with suspected CdLS, high-throughput sequencing, Sanger sequencing, and real-time qualitative PCR were used to verify the diagnosis. Variants, including six that were novel, were concentrated in the NIPBL (70%), HDAC8 (20%), and SMC3 (10%) genes. We found two nonsense, three splicing, and two deletion variants in NIPBL; a missense variant and an absence variant in HDAC8; and a missense variant in SMC3. Eleven cardinal features of CdLS were present in more than 80% of Chinese individuals. Compared with non-Chinese individuals of diverse ancestry, there were significant differences in the clinical characteristics of eight of these features. Six novel pathological variants were identified; thus, the study expanded the gene variant spectrum. Furthermore, most cardinal features of CdLS found in Chinese individuals were also found in individuals from other countries. However, there were significant differences in eight clinical features.

Liu C ，Li X ，Cui J ，Dong R ，Lv Y ，Wang D ，Zhang H ，Li X ，Li Z ，Ma J ，Liu Y ，Gai Z ... -  《Molecular Genetics & Genomic Medicine》

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 ... -  《-》