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 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 Case Report: Atypical Cornelia de Lange Syndrome

F1000Research ◽  
2015 ◽  
Vol 3 ◽  
pp. 33
Author(s):  
Vito Leanza ◽  
Gabriella Rubbino ◽  
Gianluca Leanza
Keyword(s):  
Genetic Disorder ◽  
Normal Karyotype ◽  
First Trimester ◽  
Nuchal Translucency ◽  
Cornelia De Lange Syndrome ◽  
Saddle Nose ◽  
Nasal Bridge ◽  
Venous Dilatation ◽  
Cornelia De Lange ◽  
Increased Nuchal Translucency

Cornelia de Lange Syndrome (CdLS) (also called Bushy Syndrome or Amsterdam dwarfism), is a genetic disorder that can lead to several alterations. This disease affects both physical and neuropsychiatric development. The various abnormalities include facial dysmorphia (arched eyebrows, synophrys, depressed nasal bridge, long philtrum, down-turned angles of the mouth), upper-extremity malformations, hirsutism, cardiac defects, and gastrointestinal alterations. The prevalence of this syndrome is approximately one per 15,000. Ultrasound is not the perfect means to diagnose CdLS, however, many abnormalities can be detected prenatally by scrupulous image observation.We report an atypical CdLS case characterized by increased nuchal translucency in the first trimester, normal karyotype, saddle nose, micrognathia with receding jaw, low set ears, facies senilis, arthrogryposis of the hands, absence of the Aranzio ductus venous, dilatation of gallbladder and bowel, a unique umbilical artery, increased volume of amniotic fluid, and intrauterine growth retardation ending with the interruption of pregnancy.

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 Wiedemann-Steiner Syndrome as a Differential Diagnosis of Cornelia de Lange Syndrome Using Targeted Next-Generation Sequencing: A Case Report

2020 ◽  
pp. 1-6
Author(s):  
Selma Demir ◽  
Hakan Gürkan ◽  
Veysel Öz ◽  
Sinem Yalçıntepe ◽  
Emine İ. Atlı ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Next Generation Sequencing ◽  
Growth Retardation ◽  
De Novo ◽  
Cornelia De Lange Syndrome ◽  
Next Generation ◽  
Autosomal Dominant Disorder ◽  
Targeted Next Generation Sequencing ◽  
Cornelia De Lange ◽  
Generation Sequencing

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant disorder with a variable clinical phenotype including synophrys, hypertelorism, thick eyebrows, long eyelashes, wide nasal bridge, long philtrum, hypertrichosis, growth retardation, and intellectual disability. Cornelia de Lange syndrome (CdLS) is a rare disease characterized by synophrys, long eyelashes, limb abnormalities, generalized hirsutism, growth retardation, and intellectual disability. In both WDSTS and CdLS, the malformations are due to transcriptome disturbance caused by defects in the genes encoding the components of chromatin regulation and transcription process. The overlapping features in these two syndromes may complicate the original diagnosis of a patient. Here, we report on a Wiedemann-Steiner patient found to have a de novo pathogenic <i>KMT2A</i> variation who had been clinically suspected as CdLS. We suggest that targeted next-generation sequencing is a feasible tool for the precise diagnosis of patients who have phenotypically and clinically overlapping features of CdLS and WDSTS.

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

Medicina ◽  
2020 ◽  
Vol 56 (2) ◽  
pp. 76
Author(s):  
Duong Chi Thanh ◽  
Can Thi Bich Ngoc ◽  
Ngoc-Lan Nguyen ◽  
Chi Dung Vu ◽  
Nguyen Van Tung ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Cornelia De Lange Syndrome ◽  
Heterozygous Mutation ◽  
Body Parts ◽  
Efficient Tool ◽  
Whole Exome ◽  
Cornelia De Lange ◽  
In Silico Analyses

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.

scholarly journals Atypical Cornelia de Lange Syndrome: a case report

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 33
Author(s):  
Vito Leanza ◽  
Gabriella Rubbino ◽  
Gianluca Leanza
Keyword(s):  
Genetic Disorder ◽  
First Trimester ◽  
Nuchal Translucency ◽  
Cornelia De Lange Syndrome ◽  
Saddle Nose ◽  
Nasal Bridge ◽  
Venous Dilatation ◽  
Cornelia De Lange ◽  
Facial Dysmorphia ◽  
Increased Nuchal Translucency

Cornelia de Lange Syndrome (CdLS) (also called Bushy Syndrome or Amsterdam dwarfism), is a genetic disorder that can lead to several alterations. This disease affects both physical and psychical development. The various abnormalities include facial dysmorphia (arched eyebrows, synophrys, depressed nasal bridge, long philtrum, down-turned angles of the mouth), upper-extremity malformations, hirsutism, cardiac defects, and gastrointestinal alterations. The prevalence of this syndrome is approximately one per 15,000.  Ultrasound is not the perfect means to diagnose CdLS, however, many abnormalities can be detected prenatally by scrupulous image observation.We report an atypical CdLS case characterized by increased nuchal translucency in the first trimester, normal kariotype, saddle nose, micrognathia with receding jaw, low set ears, facies senilis, arthrogryposis of the hands, absence of the Aranzio ductus venous, dilatation of gallbladder and bowel, a unique umbilical artery, increased volume of amniotic fluid, and intrauterine growth retardation ending with the interruption of pregnancy.

scholarly journals Diphenhydramine-Refractory Antipsychotic-Induced Dystonia in an Adolescent Male With Cornelia de Lange Syndrome

2019 ◽  
Vol 24 (2) ◽  
pp. 160-165 ◽  
Author(s):  
Stephen M. Small ◽  
Rachel S. Bacher
Keyword(s):  
Emergency Department ◽  
First Generation ◽  
Case Reports ◽  
Genetic Disorder ◽  
Cornelia De Lange Syndrome ◽  
Adolescent Male ◽  
Qtc Interval ◽  
Drug Induced ◽  
Iatrogenic Complications ◽  
Cornelia De Lange

Cornelia de Lange Syndrome is a rare genetic disorder that results in distinctive craniofacial deformities, developmental delay, hirsutism, and other physical abnormalities. Case reports suggest some of these patients exhibit sensitivity and paradoxical reactions to certain psychoactive drugs. This report of a 16-year-old male with Cornelia de Lange is the first to describe dystonia from a first-generation antipsychotic that did not respond to conventional treatment with diphenhydramine. The patient initially presented to the Emergency Department for agitation, which progressively worsened after administration of diphenhydramine, olanzapine, and intramuscular haloperidol. The patient returned to the Emergency Department the following day because of altered mental status and lethargy that progressed to periodic lip-smacking movements and contraction of his upper extremities. His symptoms continued despite administration of diphenhydramine and loading doses of 3 antiepileptic drugs. His abnormal labs included an elevated creatine kinase and a prolonged QTc interval on his electrocardiogram. His symptoms were later deemed a probable drug-induced dystonic reaction to haloperidol once seizures were excluded by an unremarkable electroencephalogram. This case supports previous reports suggesting an association between Cornelia de Lange and paradoxical drug reactions, and it is recommended that clinicians strongly weigh the risks of prescribing first-generation antipsychotics for this patient population. These medications should be carefully titrated, with close patient monitoring to prevent adverse drug effects and other iatrogenic complications because antidotes may be rendered ineffective by this condition.

First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia

2019 ◽  
Vol 72 (8) ◽  
pp. 558-561 ◽  
Author(s):  
Grazia Fazio ◽  
Valentina Massa ◽  
Andrea Grioni ◽  
Vojtech Bystry ◽  
Silvia Rigamonti ◽  
...  
Keyword(s):  
Paediatric Patient ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Genetic Disorder ◽  
Premature Stop Codon ◽  
Cornelia De Lange Syndrome ◽  
Sequencing Analysis ◽  
First Case ◽  
Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.

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.

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