OBJECTIVE: To explore the genetic basis for an infant featuring developmental delay, hand deformity and hypertonia of extremities. METHODS: Clinical data and peripheral blood samples of the proband and her parents were collected. Following DNA extraction, potential mutations were screened on an Ion PGM platform using a gene panel. Suspected mutation was verified by PCR and Sanger sequencing. RESULTS: A novel heterozygous nonsense mutation, c.2521C>T(p.R841X), was identified in the NIPBL gene. The mutation may cause premature termination of translation of the adhesion protein loading factor at 841st amino acids. The same mutation was not found in her parents and 931 healthy controls, and was absent from public databases including ExAC and 1000G. Bioinformatic analysis suggested the mutation to be disease causing. CONCLUSION The c.2521C>T (p.R841X) mutation of the NIPBL gene probably underlies the Cornelia De Lange syndrome in the infant. Prenatal diagnosis may be provided to this family upon their subsequent pregnancy.
De Lange Syndrome ; diagnosis ; genetics ; Female ; Heterozygote ; Humans ; Infant ; Mutation ; Pregnancy ; Prenatal Diagnosis ; Proteins ; genetics

OBJECTIVE: To analyze the clinical phenotype and results of genetic testing in three children with Cornelia de Lange syndrome (CdLS). METHODS: Clinical data of the children and their parents were collected. Peripheral blood samples of the pedigrees were collected for next generation sequencing analysis. RESULTS: The main clinical manifestations of the three children have included growth delay, mental retardation, peculiar facies and other accompanying symptoms. Based on the criteria proposed by the International Diagnostic Consensus, all three children were suspected for CdLS. As revealed by whole exome sequencing, child 1 has harbored NIPBL gene c.5567_5569delGAA insTAT missense variant, child 2 has harbored SMC1A gene c.607A>G missense variant, and child 3 has harbored HDAC8 gene c.628+1G>A splicing variant. All of the variants were de novo in origin. CONCLUSION All of the children were diagnosed with CdLS due to pathogenic variants of the associated genes, among which the variants of NIPBL and HDAC8 genes were unreported previously. Above finding has enriched the spectrum of pathogenic variants underlying CdLS.
Humans ; Cell Cycle Proteins/genetics* ; De Lange Syndrome/diagnosis* ; Genotype ; Phenotype ; Genetic Testing ; Histone Deacetylases/genetics* ; Repressor Proteins/genetics*

OBJECTIVE: To explore the genetic etiology of a fetus with Cornelia de Lange syndrome type 1. METHODS: Clinical data of the fetus was collected. Genomic DNA was extracted from amniotic fluid and peripheral blood samples of the parents and subjected to low-depth copy number variant sequencing, whole exome sequencing (WES) and Sanger sequencing. Pathogenicity of the candidate variant was predicted based on the guidelines of American College of Medical Genetics and Genomics (ACMG). Minigene assay was used to assess the effect of the variant on mRNA splicing. RESULTS: WES revealed that the fetus has harbored a heterozygous c.5808+5gG>A variant in the intron of the NIPBL gene, which was predicted to affect the mRNA splicing. The same variant was not detected in either parent. The variant was not recorded in ExAC, 1000G and dbSNP databases. Comprehensive analysis showed that the variant was deleterious and may result in skipping of exon 31 during mRNA splicing. CONCLUSION The fetus was diagnosed with Cornelia de Lange syndrome type 1. Splicing variant identified by WES may be verified by minigene assay in vitro, which can provide more evidence for the prediction of its pathogenicity.
Cell Cycle Proteins/genetics* ; De Lange Syndrome/genetics* ; Female ; Fetus ; Humans ; Mutation ; Pregnancy ; Prenatal Diagnosis ; RNA, Messenger

OBJECTIVE: To explore the prenatal ultrasonographic features and genetic basis for an abortus suspected for type II Cornelia de Lange syndrome (CdLS2). METHODS: A fetus diagnosed with CdLS2 at the Shengjing Hospital Affiliated to China Medical University on September 3, 2019 was selected as the study subject. Clinical data of the fetus and family history was collected. Following induced labor, whole exome sequencing was carried out on the abortus. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Prenatal ultrasonography (33 weeks of pregnancy) has revealed multiple anomalies in the fetus, which included slightly widened cavity of septum pellucidum, blurred corpus callosum, slightly reduced frontal lobe volume, thin cortex, fusion of lateral ventricles, polyhydramnios, small stomach bubble, and digestive tract atresia. Whole exome sequencing has revealed a heterozygous c.2076delA (p.Lys692Asnfs*27) frameshifting variant in the SMC1A gene, which was found in neither parent and was rated as pathogenic based on the guidelines of American College of Medical Genetics and Genomics (ACMG). CONCLUSION The CdLS2 in this fetus may be attributed to the c.2076delA variant of the SMC1A gene. Above finding has provided a basis for genetic counseling and assessment of reproductive risk for this family.
Pregnancy ; Female ; Humans ; Cell Cycle Proteins/genetics* ; De Lange Syndrome/diagnosis* ; Phenotype ; Ultrasonography, Prenatal ; Fetus/diagnostic imaging* ; Mutation

Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly characterized by distinctive facial features, upper limb malformations, growth and cognitive retardation. The diagnosis of the syndrome is based on the distinctive clinical features. The etiology is still not clear. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A (also called SMC1L1) and SMC3 have been suggested as probable cause of this syndrome. We experienced a case of newborn with CdLS showing bushy eyebrows and synophrys, long curly eyelashes, long philtrum, downturned angles of the mouth and thin upper lips, cleft palate, micrognathia, excessive body hair, micromelia of both hands, flexion contracture of elbows and hypertonicity. We detected a NIPBL gene mutation in a present neonate with CdLS, the first report in Korea.
Codon, Nonsense ; Codon, Terminator ; De Lange Syndrome/diagnosis/*genetics/ultrasonography ; Heterozygote ; Humans ; Infant, Newborn ; Male ; Proteins/*genetics ; Sequence Analysis, DNA ; Tomography, X-Ray Computed

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS.
Asian Continental Ancestry Group/genetics ; Base Sequence ; Cell Cycle Proteins/*genetics ; Child, Preschool ; Chromosomal Proteins, Non-Histone/*genetics ; DNA ; DNA Mutational Analysis ; De Lange Syndrome/diagnosis/*genetics ; Female ; Heterozygote ; Humans ; Male ; Pedigree ; Phenotype ; Polymorphism, Single Nucleotide ; Proteins/genetics ; Republic of Korea

OBJECTIVETo explore the clinical characteristics of Cornelia de Lange Syndrome (CdLS) and to review the latest clinical research reports.

METHODClinical and laboratory data of one case of neonatal CdLS are reported, and literature on 17 cases of CdLS in China and the international reports of the clinical and molecular biological research on this disease were reviewed.

RESULT(1) The patient was an infant with intrauterine growth retardation and born as a term small for gestational age infant with specific facial features, bone abnormality of extremities, and patent ductus arteriosus (PDA). She also had severe feeding difficulty and slow weight gain. She was followed up till 4 months of age and showed severe developmental retardation. (2) The total number of past reported case of CdLS in China was 17 with a male to female ratio of 6:12. The average age of diagnosis was 17 months. The following specific facial features could be observed: synophrys, long and curved eyelashes, hirsutism, microcephalus, low hairline, broad depressed nasal bridge, long prominent philtrum, and high palate. Most of the patients were complicated with mental retardation, recurrent vomiting or feeding difficulty, abnormal muscle tone, cutis marmorata, hypophalangism, and genitalia anomaly. Clinical manifestations of Chinese patients were similar to those of the overseas reports. The karyotype of 15 cases was investigated and was normal. The etiology of CdLS is unknown. There is no specific treatment. The commonest causes of death are lung diseases caused by gastroesophageal reflex/aspirate related pneumonia.

CONCLUSIONTypical clinical manifestations of CdLS are specific facial features (mainly synophrys, long and curved eyelashes, long prominent philtrum), complications of multi-system malformations (mainly growth and developmental retardation, esophagogastric reflex, hypophalangism), related gene mutations occurred in NIPBL, SMC1A, and SMC3 gene.

Abnormalities, Multiple ; diagnosis ; genetics ; pathology ; Cause of Death ; Child ; Child, Preschool ; Craniofacial Abnormalities ; diagnosis ; genetics ; pathology ; De Lange Syndrome ; diagnosis ; genetics ; pathology ; Ductus Arteriosus, Patent ; etiology ; Female ; Genetic Testing ; Humans ; Infant ; Infant, Newborn ; Intellectual Disability ; etiology ; Magnetic Resonance Imaging ; Male ; Mutation ; Proteins ; genetics ; Severity of Illness Index