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

2021 ◽  
Vol 12 ◽  
Author(s):  
Ran Li ◽  
Bowen Tian ◽  
Hanting Liang ◽  
Meiping Chen ◽  
Hongbo Yang ◽  
...  
Keyword(s):  
Literature Review ◽  
Short Stature ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Cornelia De Lange Syndrome ◽  
Gene Variants ◽  
Whole Exome ◽  
Development Delay ◽  
Cornelia De Lange ◽  
Verbal Development

PurposeCornelia 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.MethodsWe 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.ResultsA 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.ConclusionThis 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.

scholarly journals Clinical and molecular analysis in a cohort of Chinese children with Cornelia de Lange syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Qun Li ◽  
Guoying Chang ◽  
Lei Yin ◽  
Juan Li ◽  
Xiaodong Huang ◽  
...  
Keyword(s):  
Clinical Features ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Genetic Variations ◽  
Chinese Children ◽  
Chinese Patients ◽  
Cornelia De Lange Syndrome ◽  
Gene Variants ◽  
Wide Range ◽  
Cornelia De Lange

AbstractCornelia de Lange Syndrome (CdLS) is a rare genetic disorder, which causes a range of physical, cognitive, and medical challenges. To retrospectively analyze the clinical characteristics and genetic variations of Chinese patients, and to provide experience for further diagnosis and treatment of CdLS in Chinese children, we identified 15 unrelated Chinese children who presented with unusual facial features, short stature, developmental delay, limb abnormalities, and a wide range of health conditions. In this study, targeted-next generation sequencing was used to screen for causal variants and the clinically relevant variants were subsequently verified using Sanger sequencing. DNA sequencing identified 15 genetic variations, including 11 NIPBL gene variants, two SMC1A gene variants, one RAD21 gene variant, and one HDAC8 variant. The phenotype of these patients was summarized and differences between this cohort and another four groups were compared. The clinical manifestations of the patients in this cohort were mostly consistent with other ethnicities, but several clinical features in our cohort had different frequencies compared with other groups. We identified 15 deleterious variants of which 11 were novel. Variants in the NIPBL gene were the most common cause in our cohort. Our study not only expands upon the spectrum of genetic variations in CdLS, but also broadens our understanding of the clinical features of CdLS.

scholarly journals Patients Carrying 9q31.1-q32 Deletion Share Common Features with Cornelia de Lange Syndrome

2015 ◽  
Vol 35 (1) ◽  
pp. 270-280 ◽  
Author(s):  
Ruixue Cao ◽  
Tian Pu ◽  
Shaohai Fang ◽  
Fei Long ◽  
Jing Xie ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Limb Development ◽  
Cornelia De Lange Syndrome ◽  
Pcr Analysis ◽  
Cgh Array ◽  
Whole Exome ◽  
Cornelia De Lange ◽  
Development Objectives ◽  
Structural Maintenance Of Chromosomes

Background: Cornelia de Lange Syndrome (CdLS) is a rare but severe clinically heterogeneous developmental disorder characterized by facial dysmorphia, growth and cognitive retardation, and abnormalities of limb development. Objectives: To determine the pathogenesis of a patient with CdLS. Methods: We studied a patient with CdLS by whole exome sequencing, karyotyping and Agilent CGH Array. The results were confirmed by quantitative real-time PCR analysis of the patient and her parents. Further comparison of our patient and cases with partially overlapping deletions retrieved from the literature and databases was undertaken. Results: Whole exome sequencing had excluded the mutation of cohesion genes such as NIPBL,SMC1A and SMC3. The result of karyotyping showed a deletion of chromosome 9q31.1-q32 and the result of Agilent CGH Array further displayed a 12.01-Mb region of deletion at chromosome bands 9q31.1-q32. Reported cases with the deletion of 9q31.1-q32 share similar features with our CdLS patient. One of the genes in the deleted region, SMC2, belongs to the Structural Maintenance of Chromosomes (SMC) family and regulates gene expression and DNA repair. Conclusions: Patients carrying the deletion of 9q31.1-q32 showed similar phenotypes with CdLS.

Clinical Diagnosis of Classical Cornelia de Lange Syndrome Made From Postmortem Examination of Second Trimester Fetus With Novel NIPBL Pathogenic Variant

2019 ◽  
Vol 22 (5) ◽  
pp. 475-479 ◽  
Author(s):  
Jennifer Hague ◽  
Philip Twiss ◽  
Zoe Mead ◽  
Soo-Mi Park
Keyword(s):  
Clinical Diagnosis ◽  
Upper Limb ◽  
Growth Retardation ◽  
Postmortem Examination ◽  
Pathogenic Variant ◽  
Cornelia De Lange Syndrome ◽  
Molecular Testing ◽  
Intrauterine Death ◽  
Second Trimester ◽  
Cornelia De Lange

Classical Cornelia de Lange syndrome (CdLS) is a rare genetic disorder which is associated with distinctive facial features, growth retardation, significant intellectual disability and global developmental delay, hirsutism, and upper-limb reduction defects. Classical CdLS is associated with pathogenic variants in NIPBL. We present a clinical diagnosis of classical CdLS made in a second trimester male fetus with advanced maceration who had undergone intrauterine death at 15 + 6 weeks gestation. The diagnosis was suspected after multiple congenital anomalies were identified on fetal postmortem examination. These included intrauterine growth retardation, upper limb anomalies, ventricular septal defect and diaphragmatic hernia, and skeletal and genitourinary abnormalities. Related prenatal screening findings included a raised nuchal translucency and low maternal serum pregnancy-associated plasma protein-A. Targeted molecular sequencing of genes associated with CdLS identified a novel de novo frameshift pathogenic variant in NIPBL, which confirmed the diagnosis. This report describes our case and reviews the current literature on prenatal diagnosis of CdLS. In summary, we demonstrate that clinical diagnosis of CdLS in a second trimester fetus, through postmortem examination findings, is possible, with confirmation through molecular testing.

scholarly journals Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Paolo Grazioli ◽  
Chiara Parodi ◽  
Milena Mariani ◽  
Daniele Bottai ◽  
Elisabetta Di Fede ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Cellular Proliferation ◽  
Chemical Activation ◽  
Clinical Manifestations ◽  
Experimental Models ◽  
Proliferation Rate ◽  
Cornelia De Lange Syndrome ◽  
Canonical Wnt Pathway ◽  
Cornelia De Lange ◽  
Canonical Wnt

AbstractCornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

scholarly journals Case Report: Prenatal Whole-Exome Sequencing to Identify a Novel Heterozygous Synonymous Variant in NIPBL in a Fetus With Cornelia de Lange Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Fengchang Qiao ◽  
Cuiping Zhang ◽  
Yan Wang ◽  
Gang Liu ◽  
Binbin Shao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Cornelia De Lange Syndrome ◽  
Splice Donor Site ◽  
Synonymous Mutations ◽  
Craniofacial Dysmorphism ◽  
Whole Exome ◽  
Synonymous Variant ◽  
Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by a wide spectrum of abnormalities, including craniofacial dysmorphism, upper limb anomalies, pre- and post-natal growth restrictions, hirsutism and intellectual disability. Approximately 60% of cases are caused by NIPBL variants. Herein we report on a prenatal case presented with bilateral upper-extremity malformations and cardiac defects. Whole-exome sequencing (WES) was performed on the fetus–parental trio and a de novo heterozygous synonymous variant in NIPBL [chr5:37020979; NM_133433.4: c.5328G>A, p. (Gln1776=)] was identified. Reverse transcriptase–polymerase chain reaction (RT–PCR) was conducted to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (103 bp) by disrupting the splice-donor site and changed the reading frame with the insertion of at least three stop codons. Our finding not only expands the mutation spectrum of NIPBL gene but also establishes the crucial role of WES in searching for underlying genetic variants. In addition, our research raises the important issue that synonymous mutations may be potential pathogenic variants and should not be neglected in clinical diagnoses.

scholarly journals BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Pablo García-Gutiérrez ◽  
Mario García-Domínguez
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Complex Function ◽  
Clinical Manifestations ◽  
Cornelia De Lange Syndrome ◽  
Cohesin Complex ◽  
Developmental Defects ◽  
Cornelia De Lange

Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

scholarly journals Lithium ameliorates Cornelia de Lange syndrome associated phenotypes in experimental models

2020 ◽  
Author(s):  
Paolo Grazioli ◽  
Chiara Parodi ◽  
Milena Mariani ◽  
Daniele Bottai ◽  
Elisabetta Di Fede ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Cellular Proliferation ◽  
Chemical Activation ◽  
Clinical Manifestations ◽  
Experimental Models ◽  
Proliferation Rate ◽  
Cornelia De Lange Syndrome ◽  
Canonical Wnt Pathway ◽  
Cornelia De Lange ◽  
Canonical Wnt

ABSTRACTCornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from deregulation of developmental pathways, inclusive of the canonical WNT pathway.We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin.Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

scholarly journals Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Peng ◽  
Changbiao Liang ◽  
Hui Xi ◽  
Shuting Yang ◽  
Jiancheng Hu ◽  
...  
Keyword(s):  
Growth Retardation ◽  
De Novo ◽  
Genetic Disorder ◽  
Snp Array ◽  
Nuchal Translucency ◽  
Chinese Patients ◽  
Cornelia De Lange Syndrome ◽  
Whole Exome ◽  
Limb Malformations ◽  
Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. Mutation in the NIPBL gene accounts for nearly 60% of the cases. This study reports the clinical and genetic findings of three cases of CdLS from unrelated Chinese families. Clinically, all the three cases were classified as classic CdLS based on the cardinal (distinctive facial features and limb malformations) and suggestive (developmental delay, growth retardation, microcephaly, hirsutism, etc.) manifestations. SNP array detected a novel de novo heterozygous microdeletion of 0.2 Mb [arr[GRCh37]5p13.2(36848530_37052821) × 1] that spans the first 43 exons of NIPBL in the fetus with nuchal translucency thickening in case 1. Whole-exome sequencing in family trios plus Sanger sequencing validation identified a de novo heterozygous NIPBL c.5566G>A (p.R1856G) mutation in the fetus with intrauterine growth retardation in case 2 and a novel de novo heterozygous NIPBL c.448dupA (p.S150Kfs*23) mutation in the proband (an 8-month-old girl) in case 3. The cases presented in this study may serve as references for increasing our understanding of the mutation spectrum of NIPBL in association with CdLS.

scholarly journals A New Mutation Identified by Whole Exome Sequencing in a Cornelia de Lange Syndrome Newborn

2018 ◽  
Vol 131 (19) ◽  
pp. 2384-2385
Author(s):  
Hua Zhang ◽  
Li-Ming Yang ◽  
Lu Yuan ◽  
Xin Tan ◽  
Fu-Qing Zhang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cornelia De Lange Syndrome ◽  
New Mutation ◽  
Whole Exome ◽  
Cornelia De Lange
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