Cervical spine malformation in cornelia de lange syndrome: A report of three patients

Bettini, Laura Rachele; Locatelli, Laura; Mariani, Milena; Cianci, Paola; Giussani, Carlo; Canonico, Francesco; Cereda, Anna; Russo, Silvia; Gervasini, Cristina; Biondi, Andrea; Selicorni, Angelo

doi:10.1002/ajmg.a.36457

Cited by 7 publications

(8 citation statements)

References 25 publications

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“…Unusual anomalies in the RAD21 cases are vertebral anomalies (clefts and hemivertebrae). There is a single individual with a NIPBL variant and Klippel-Feil anomaly (personal observation RCH), and upper cervical spine malformations have been reported in other patients with NIPBL variants as well (Bettini et al 2014). Malformations of structures derived from the embryonic foregut are relatively frequent in RAD21 patients and have only rarely been described in CdLS (Hamilton et al 2014;Kang et al 2018;Mende et al 2012).…”

Section: Comparison To Phenotypes Of Nipbl and Smc1a Variantsmentioning

confidence: 97%

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.Zeynep Tümer and Raoul C. Hennekam contributed equally.

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Section: Comparison To Phenotypes Of Nipbl and Smc1a Variantsmentioning

confidence: 97%

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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“…Experience of scoliosis surgery is limited, but our mutual experience indicates that standard management is effective, taking prognosis with respect to development and mobility into account. Spine malformations are extremely rare and typically asymptomatic 121 , with kyphosis present in one-quarter of these individuals 118 . Flexion contractures have been reported in 18-25% of individuals with CdLS, particularly in the knees, which can interfere with ambulation, but also in the elbow and/or hip, as have tight Achilles tendons 118,122 .…”

Section: Orthopaedicsmentioning

confidence: 99%

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

et al. 2018

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Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

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“…The replacement of arginine with a stop codon lead to an early termination of the NIPBL protein at residue 868 (Figure 2d). This substitution was reported in ClinVar database (ID: VCV000096337.2) as a pathogenic mutation and in the dbSNP database (ID: rs398124466) [19].…”

Section: Presentation Of Case Reportsmentioning

confidence: 85%

De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

et al. 2020

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Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.

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Cervical spine malformation in cornelia de lange syndrome: A report of three patients

Cited by 7 publications

References 25 publications

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

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