A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.

Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.

Gudmundsson S ，Annerén G ，Marcos-Alcalde Í ，Wilbe M ，Melin M ，Gómez-Puertas P ，Bondeson ML ... -  《-》

Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case.

Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. Mutations in the NIPBL gene predominate; however, mutations in other cohesin complex genes have also been implicated, particularly in atypical and mild CdLS cases. Missense mutations and whole gene deletions in RAD21 have been identified in children with growth retardation, minor skeletal anomalies and facial features that overlap findings in individuals with CdLS. We report the first intragenic deletion and frameshift mutations identified in RAD21 in two patients presenting with atypical CdLS. One patient had an in-frame deletion of exon 13, while the second patient had a c.592_593dup frameshift mutation. The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first patient being milder than the second. The in-frame deletion mutation was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. This study expands the spectrum of RAD21 mutations and emphasizes the clinical utility of performing RAD21 mutation analysis in patients presenting with atypical forms of CdLS. Moreover, the variability of clinical presentation within families and low penetrance of mutations as well as the significance of performing molecular genetic testing in mildly affected patients are discussed.

Minor A ，Shinawi M ，Hogue JS ，Vineyard M ，Hamlin DR ，Tan C ，Donato K ，Wysinger L ，Botes S ，Das S ，Del Gaudio D ... -  《-》

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 ... -  《-》

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 ... -  《-》

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Kaur M ，Blair J ，Devkota B ，Fortunato S ，Clark D ，Lawrence A ，Kim J ，Do W ，Semeo B ，Katz O ，Mehta D ，Yamamoto N ，Schindler E ，Al Rawi Z ，Wallace N ，Wilde JJ ，McCallum J ，Liu J ，Xu D ，Jackson M ，Rentas S ，Tayoun AA ，Zhe Z ，Abdul-Rahman O ，Allen B ，Angula MA ，Anyane-Yeboa K ，Argente J ，Arn PH ，Armstrong L ，Basel-Salmon L ，Baynam G ，Bird LM ，Bruegger D ，Ch'ng GS ，Chitayat D ，Clark R ，Cox GF ，Dave U ，DeBaere E ，Field M ，Graham JM Jr ，Gripp KW ，Greenstein R ，Gupta N ，Heidenreich R ，Hoffman J ，Hopkin RJ ，Jones KL ，Jones MC ，Kariminejad A ，Kogan J ，Lace B ，Leroy J ，Lynch SA ，McDonald M ，Meagher K ，Mendelsohn N ，Micule I ，Moeschler J ，Nampoothiri S ，Ohashi K ，Powell CM ，Ramanathan S ，Raskin S ，Roeder E ，Rio M ，Rope AF ，Sangha K ，Scheuerle AE ，Schneider A ，Shalev S ，Siu V ，Smith R ，Stevens C ，Tkemaladze T ，Toimie J ，Toriello H ，Turner A ，Wheeler PG ，White SM ，Young T ，Loomes KM ，Pipan M ，Harrington AT ，Zackai E ，Rajagopalan R ，Conlin L ，Deardorff MA ，McEldrew D ，Pie J ，Ramos F ，Musio A ，Kline AD ，Izumi K ，Raible SE ，Krantz ID ... -  《-》