An Autosomal Recessive form of Cornelia de Lange Syndrome Due to Mutations in TRMT61A Gene: A Case Report

Rna Modification ◽

Compound Heterozygous ◽

Specific Pcr ◽

Gastrointestinal Problems ◽

Cornelia De Lange ◽

Coding Variants

Background: Cornelia de Lange syndrome is a rare genetic disorder presenting with craniofacial dysmorphia, developmental delay, intellectual disabilities, upper limb abnormalities and gastrointestinal problems. The disease is genetically heterogenous and the underlying genetic cause in unknown in around 30% of the cases. Case Presentation: A Palestinian family visited our department for genetic counseling. The non-consanguineous parents have only two (4 and 2 years old) daughters, both presented with features consistent with Cornelia de Lange syndrome. Whole exome sequencing revealed two previously unknown coding variants in the autosomal TRMT61A, a gene that has not been linked to any human disease before. TRMT61A codes for the catalytic subunit of tRNA (adenine-N1-)-methyltransferase. The mother harbored an in-frame deletion variant c.478_483delCGCACC (p.R160_T161del), whereas the father carried a missense variant c.323G>T (p.C108F). Both variants are novel and were predicted as "damaging". So far, no autosomal recessive forms of the disease has been described in the literature. The carrier states of the parents and the existence of the two variants in compound heterozygous forms in both girls was further confirmed by allele-specific PCR. In their next pregnancy, prenatal diagnosis indicated that the fetus is a carrier of the mother's variant and the pregnancy culminated in the birth of a healthy baby girl. Conclusion: It can be concluded that the TRMT61A mutations are the cause of the disease features observed in this family and supports the proposal that RNA modification defects are involved in the molecular pathogenesis of Cornelia de Lange syndrome.

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

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-24.2.160 ◽

2019 ◽

Vol 24 (2) ◽

pp. 160-165 ◽

Cited By ~ 1

Author(s):

Stephen M. Small ◽

Rachel S. Bacher

Keyword(s):

Emergency Department ◽

First Generation ◽

Case Reports ◽

Genetic Disorder ◽

Adolescent Male ◽

Qtc Interval ◽

Drug Induced ◽

Iatrogenic Complications ◽

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

Journal of Clinical Pathology ◽

10.1136/jclinpath-2019-205707 ◽

2019 ◽

Vol 72 (8) ◽

pp. 558-561 ◽

Cited By ~ 1

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 ◽

Sequencing Analysis ◽

First Case ◽

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.

Brachmann Cornelia De Lange Syndrome: A Tailored Approach for Assessment and Intervention Using the Griffiths III

Journal of Studies in Education ◽

10.5296/jse.v10i3.17202 ◽

2020 ◽

Vol 10 (3) ◽

pp. 43

Author(s):

Jennifer M Jansen ◽

Elizabeth Mary Green ◽

Louise A Stroud ◽

Mark B Watson

Keyword(s):

Test Scores ◽

Genetic Disorder ◽

Intervention Strategy ◽

Clinical Population ◽

Level Of Functioning ◽

Intervention Plan ◽

Developmental Functioning ◽

Tailored Approach ◽

The process of evaluation and intervention of an atypical child poses challenges in a number of areas. These challenges include measures that are not normed for a clinical population, the interpretation of test scores and the use of test scores to devise a meaningful individualized intervention plan that also takes into account sociocultural issues affecting family functioning. To highlight these challenges, an evaluation of a 7-year 1month old girl with Brachmann Cornelia De Lange Syndrome is described using the Griffiths III Scales of Child Development together with the Conners 3- Parent Teacher Surveys and the Vineland Adaptive Scales. The Griffiths III results confirmed a pattern of global delay in all areas of her developmental functioning. The child demonstrated difficulty with the medical and behavioural manifestations of her genetic disorder that needed to be factored into the intervention strategy. The results guided the interventions of different professionals in developing an individualised intervention plan considering the above-identified challenges. The article serves thus as a guide on how to work creatively to determine the level of functioning of an atypical child in the light of the absence of normed measures for such children.

A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

Journal of Pediatric Genetics ◽

10.1055/s-0040-1718534 ◽

2020 ◽

Author(s):

Haydar Bağış ◽

Özden Öztürk ◽

Semih Bolu ◽

Bayram Taşkın

Keyword(s):

Novel Mutation ◽

Genetic Disorder ◽

Gene Mutations ◽

The Other ◽

Other Hand ◽

Wide Range ◽

AbstractThe Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. CdLS is due to mutations in one of the following genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. On the other hand, 10q11.2 deletions cause a wide range of presentations in patients. Approximately 40 cases with variable deletions of 10q11.2 have been reported in literature. Some of the reported cases involve the coexistence of duplication or deletion affecting one copy of the chromosome. However, deletion of chromosome 10q11.22-q11.23 and CdLS syndrome caused by NIPBL gene mutations have not been reported previously. This report, therefore, is the first to report their coexistence together.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0412 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Radha Rama Devi Akella

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Genetic Diagnosis ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Postnatal Growth ◽

Compound Heterozygous ◽

Case Presentation ◽

Whole Exome ◽

Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report

BMC Neurology ◽

10.1186/s12883-021-02050-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ke Tong ◽

Geng-Sheng Yu

Keyword(s):

Sanger Sequencing ◽

Autosomal Recessive ◽

Missense Variant ◽

Serum Creatine Kinase ◽

Accurate Diagnosis ◽

Strenuous Exercise ◽

Compound Heterozygous ◽

Case Presentation ◽

Heterozygous Variant ◽

Recurrent Rhabdomyolysis

Abstract Background LPIN1-related acute recurrent rhabdomyolysis (RM), first reported in 2008, is an autosomal recessive inherited metabolic disease. In recent years, LPIN1 gene variants have been identified as one of the main causes of severe RM in children in Western countries. The disease is extremely rare in China, and we report a case of acute recurrent RM caused by a novel compound heterozygous LPIN1 variant. Case presentation A 15-year-old Chinese boy presented with myalgia after strenuous exercise, accompanied by transient increases in serum creatine kinase and myoglobin and persistent hyperuricaemia and hyperbilirubinaemia. Genetic analysis using high-throughput genomic sequencing and Sanger sequencing revealed that there was a compound heterozygous variant in the LPIN1 gene of the proband: the paternal c.2047A > G(p.I683V) was an unreported missense variant, and the maternal c.2107_2108 insAGG(p.Q703delin sQE) was an unreported in-frame variant. Conclusions In children with RM, LPIN1 variants should always be considered in the differential diagnosis. The clinical features of our case are atypical, which highlights the importance of an accurate diagnosis by genetic testing. If detected early, the condition may be controlled, and the prognosis may be improved.

Case Report: Atypical Cornelia de Lange Syndrome

F1000Research ◽

10.12688/f1000research.3-33.v2 ◽

2015 ◽

Vol 3 ◽

pp. 33

Author(s):

Vito Leanza ◽

Gabriella Rubbino ◽

Gianluca Leanza

Keyword(s):

Genetic Disorder ◽

Normal Karyotype ◽

First Trimester ◽

Nuchal Translucency ◽

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.

A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome

Cellular Physiology and Biochemistry ◽

10.1159/000491613 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2388-2395 ◽

Cited By ~ 3

Author(s):

Xueren Gao ◽

Zhuo Huang ◽

Yanjie Fan ◽

Yu Sun ◽

Huili Liu ◽

...

Keyword(s):

Missense Mutation ◽

X Chromosome ◽

Genetic Disorder ◽

Sodium Dodecyl ◽

Pathogenic Mutation ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Background/Aims: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder classically characterized by distinctive facies, growth retardation, intellectual disability, feeding difficulties, and multiple organ system anomalies. Previously, the diagnosis of CdLS was based mainly on identifying the typical phenotype in patients. However, with the advances in clinical molecular genetic diagnostic techniques, more patients, especially patients with milder phenotypes, are being diagnosed from detecting pathogenic mutation. Methods: Pathogenic mutation in a female patient with a milder phenotype was detected using whole-exome sequencing (WES), and was further characterized using bioinformatic analysis and in vitro functional experiments, including X-chromosome inactivation analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and enzyme activity assay. Results: This patient was found to harbor a novel missense mutation (c.806T>G, p.I269R) in the coding region of the HDAC8 gene, which was predicted to be pathogenic. Compared with other CdLS patients with HDAC8 mutation, the patient lacked typical facies, including synophrys and arched eyebrows. In vitro functional experiments showed the presence of skewed X-chromosome inactivation. Furthermore, the novel mutation decreased the dissolubility and enzymatic activity of HDAC8 protein. Conclusions: The present study identified a novel missense mutation (c.806T>G, p.I269R) in the HDAC8 gene leading to CdLS, which not only provided strong evidence for diagnosis in this present patient, but also expanded the spectrum of pathogenic mutations for CdLS.

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

Scientific Reports ◽

10.1038/s41598-020-78205-5 ◽

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 ◽

Gene Variants ◽

Wide Range ◽

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.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.699894 ◽

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 ◽

Whole Exome ◽

Limb Malformations ◽

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.