De Lange Syndrome Research Articles

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review.

BackgroundCornelia de Lange syndrome (CdLS) is a genetic disorder caused by variants in cohesion genes including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. According to the 2018 consensus statement, a patient with clinical scored ≥ 11 points could be diagnosed as CdLS. However, some variants in non-cohesion genes rather than cohesion genes can manifest as phenotypes of CdLS.ObjectivesThis study describes six variants of non-cohesion genes (KDM6A, KMT2D, KMT2A ANKRD11, and UBE2A), and assesses the reliability of 11-points scale criteria in the clinical diagnosis of CdLS.MethodsWhole-exome sequencing (WES) was performed on six patients with features of CdLS. Phenotypic and genotypic spectra of 40 previously reported patients with features of CdLS caused by non-cohesion genes variants and 34 previously reported patients with NIPBL variants were summarized. Clinical score comparison among patients with NIPBL variants versus those with variants in non-cohesin genes was performed.ResultsVariants in non-cohesion genes were found in six patients [KMT2A (n = 2), KMT2D, ANKRD11, KDM6A, and UBE2A]. Of them, four variants (KMT2A c.7789C > T, ANKRD11 c.1757_1776del, KDM6A c.655-1G > A, and UBE2A c.439C > T) were novel. Combining with previously reported cases, 46 patients with phenotypes of CdLS caused by variants in 20 non-cohesion genes are now reported. From this total cohort, the average clinical score of patients in ANKRD11 cohort, SETD5 cohort, and AFF4 cohort was statistically lower than those in NIPBL cohort (8.92 ± 1.77 vs. 12.23 ± 2.58, 7.33 ± 2.52 vs. 12.23 ± 2.58, 5.33 ± 1.53 vs. 12.23 ± 2.58; p < 0.05). The average clinical score of KMT2A cohort, EP300 cohort, and NIPBL cohort had not significantly different from (11 ± 2.19 vs. 12.23 ± 2.58, 10 ± 4.58 vs. 12.23 ± 2.58; p > 0.05).ConclusionWe described 4 novel variants of non-cohesion genes in six Chinese patients with phenotypes of CdLS. Of note, three genes (KMT2D, KDM6A, and UBE2A) causing features of CdLS have never been reported. The proposed clinical criteria for CdLS needed to be updated and refined, insofar as WES was necessary to confirm the diagnosis of CdLS. Our study expanded the spectra of non-cohesion genetic variations in patients with features of CdLS.

Establishment of a human induced pluripotent stem cell line, KMUGMCi002-A, from a patient bearing a heterozygous c.6362_6364del mutation in the NIPBL gene leading Cornelia de Lange syndrome (CdLS)

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomalies syndrome caused by mutations in the cohesion complex. The mutations in NIPBL, one of cohesion regulatory proteins, are the most frequent cause of CdLS. The peripheral blood mononuclear cells (PBMCs) from a patient carrying a heterozygous 3 bp deletion in Exon 37 of the NIPBL gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. The deleted mutation in NIPBL will cause the abnormal truncated protein, which is known to associated with CdLS. The established human induced pluripotent cell (hiPSC) line will enable proper in vitro disease modelling of CdLS.Resource Table:

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae.

Eco1/Ctf7 is a highly conserved acetyltransferase that activates cohesin complexes and is critical for sister chromatid cohesion, chromosome condensation, DNA damage repair, nucleolar integrity, and gene transcription. Mutations in the human homolog of ECO1 (ESCO2/EFO2), or in genes that encode cohesin subunits, result in severe developmental abnormalities and intellectual disabilities referred to as Roberts syndrome and Cornelia de Lange syndrome, respectively. In yeast, deletion of ECO1 results in cell inviability. Codeletion of RAD61 (WAPL in humans), however, produces viable yeast cells. These eco1 rad61 double mutants, however, exhibit a severe temperature-sensitive growth defect, suggesting that Eco1 or cohesins respond to hyperthermic stress through a mechanism that occurs independent of Rad61. Here, we report that deletion of the G1 cyclin CLN2 rescues the temperature-sensitive lethality otherwise exhibited by eco1 rad61 mutant cells, such that the triple mutant cells exhibit robust growth over a broad range of temperatures. While Cln1, Cln2, and Cln3 are functionally redundant G1 cyclins, neither CLN1 nor CLN3 deletions rescue the temperature-sensitive growth defects otherwise exhibited by eco1 rad61 double mutants. We further provide evidence that CLN2 deletion rescues hyperthermic growth defects independent of START and impacts the state of chromosome condensation. These findings reveal novel roles for Cln2 that are unique among the G1 cyclin family and appear critical for cohesin regulation during hyperthermic stress.

Lobster Claw Hand Deformity - Cornelia de Lange Syndrome

Background: Cornelia de Lange syndrome is a genetic syndrome characterized by intellectual disability, facial features with synorphrys or fused eyebrows, upper limb anomalies and atypical growth. It is caused by spontaneous mutations in genes responsible for structural or regulatory function of cohesin complex.&#x0D; Report: We present two newborns cases admitted to our NICU with characteristic dysmorphic features of microcephaly, ectrodactyly and thick eyebrows. One baby also had associated congenital heart defect and sensorineural hearing loss. Both babies are under followup with developmental early intervention programs. Parents were offered genetic counselling for future pregnancies.&#x0D; Conclusion: Cornelia de Lange is predominantly a clinical diagnosis by identifying typical dysmorphic features. Labelling a syndromic diagnosis helps to provide genetic counselling to the parents, identify associated co-morbidities at earlier stages and improve the quality of living of such children.

Gastrostomy and congenital anomalies: a European population-based study

ObjectiveTo report and compare the proportion of children with and without congenital anomalies undergoing gastrostomy for tube feeding in their first 5 years.MethodsA European, population-based data-linkage cohort study (EUROlinkCAT). Children...

Usefulness of auditory brainstem response in Cornelia de Lange Syndrome

Usefulness of auditory brainstem response in Cornelia de Lange Syndrome

Subclinical myocardial dysfunction is revealed by speckle tracking echocardiography in patients with Cornelia de Lange syndrome

This study assesses a possible cardiac dysfunction in individuals with Cornelia de Lange syndrome (CdLS) without diagnosed congenital heart disease (CHD) and its association with other factors. Twenty patients and 20 controls were included in the study divided into three age-dependent groups (A: < 10 yrs, B: 10–20 yrs, C: > 20 yrs), and were evaluated using conventional echocardiography, tissue doppler imaging (TDI), two-dimensional speckle tracking and genetic and biochemical analyses. The left ventricular global longitudinal strain (GLS) was altered (< 15.9%) in 55% of patients, being pathological in the older group (A: 19.7 ± 6.6; B: -17.2 ± 4.7; C: -13.6 ± 2.9). The speckle tracking technique revealed a downward trend in the values of strain, strain rate and velocity, especially in the oldest group. Likewise, the ejection fraction (LVEF) and shortening fraction (LVFS) values, although preserved, also showed a decreased with age (p < 0.05). The analytical markers of cardiovascular risk and cardiac function showed no alterations. The molecular analyses revealed 16 individuals carrying pathogenic variants in NIPBL, two with variants in SMC1A, one with a variant in RAD21 and one with a HDAC8 variant. This is the first systematic approach that demonstrates that individuals with CdLS may present early cardiomyopathy, which can be detected by speckle tracking technique even before the appearance of clinical symptoms and the alteration of other echocardiographic or analytical parameters. For all these reasons, cardiological followup is suggested even in the absence of CHD, especially from adolescence onwards.

Prenatal diagnosis of Cornelia de Lange syndrome from 12 to 17weeks' gestation.

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Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.

Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.

Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a rare, multifactorial, multisystem disorder that affects approximately 1/10,000-100,000 newborns. Mutations and/or variants have been identified in seven genes that have been associated with the diagnosis of this disorder. As all of them affect the cohesin complex, CdLS is also referred to as a "transcriptomopathy" or "cohesinopathy." The phenotype and presentation vary greatly, though there is a classic phenotype that includes a distinctive craniofacial appearance and growth pattern in addition to limb malformations. Because there are multiple overlapping phenotypes with Cornelia de Lange syndrome and other syndromes and sequences, early diagnosis and management of Cornelia de Lange syndrome is imperative. This will enhance the quality of life for individuals with this disorder, as many are now likely to live well into adulthood.

Pancreatic neuroendocrine tumor in a 27-year-old patient with Cornelia de Lange syndrome: a case report

Pancreatic neuroendocrine tumor in a 27-year-old patient with Cornelia de Lange syndrome: a case report

(PO-191) Seizures or Behavioral Disturbances? A case report on neuropsychiatric manifestations of Cornelia de Lange Syndrome and management in an Emergency Department Consultation-Liaison Setting

(PO-191) Seizures or Behavioral Disturbances? A case report on neuropsychiatric manifestations of Cornelia de Lange Syndrome and management in an Emergency Department Consultation-Liaison Setting

Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study.

BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.

A Novel de Novo Variant in 5' UTR of the NIPBL Associated with Cornelia de Lange Syndrome.

Background: Cornelia de Lange syndrome (CdLS) is a genetic syndrome characterized by intellectual disability, special facial features, growth retardation, feeding difficulties, and multiple organ system abnormalities. NIPBL variants occur in approximately 80% of CdLS cases. Aims: We report a novel de novo heterozygous pathogenic variant in the NIPBL and its association with CdLS. We also examined the key regulatory sequences of the 5′ untranslated region in NIPBL mRNA. Few studies have reported mutation sites in the 5′ untranslated region (UTR) of the NIPBL that result in CdLS. Methods: The patient’s medical history, clinical manifestations, physical examination, laboratory examination, Griffiths development assessment scale—Chinese version, and cardiac B-ultrasound were examined. Mutation screening was conducted using trio whole exome sequencing (trio-WES) and Sanger sequencing. Quantitative PCR was performed to measure the NIPBL expression in peripheral blood mononuclear cells. A Dual-Luciferase reporter assay was conducted to evaluate the transcription of truncated mutants. Results: The proband showed characteristics of CdLS including thick eyebrows, a concave nasal ridge, long and smooth philtrum, downturned corners of the mouth, intellectual disability, postnatal growth retardation, and a short fifth toe. A novel de novo heterozygous pathogenic variant in the NIPBL (c.-467C > T) was identified. A Dual-Luciferase reporter gene assay showed that SPO1 (-490 bp to -360 bp) and SPO3 (-490 bp to -401 bp) induced the highest activity. Conclusions: We found a novel de novo heterozygous pathogenic variant (c.-467C > T) in the NIPBL resulting in CdLS. Our findings expand the spectrum of pathogenic mutations for CdLS. Our in vitro experiments elucidated important regulatory sequences in the 5′ UTR of the NIPBL.

Age-related hallmarks of psychopathology in Cornelia de Lange and Rubinstein-Taybi syndromes

Background and aimThere is mounting evidence highlighting that Cornelia de Lange Syndrome (CdLS) and Rubinstein-Taybi Syndrome’s (RSTS) behavioral phenotypes are not stable over individual developmental trajectories and that several psychiatric disorders might arise with age. Our study aims to examine the specific hallmarks of psychopathology and behavioral phenotypes in four different age ranges: infancy and toddlerhood, early childhood, middle childhood, and adolescence, in both genetic syndromes. MethodThe sample included 44 patients with CdLS (48% boys, age = 6.67 ± 4.36) and 31 with RSTS (48% boys, age = 6.89 ± 4.58) recruited through follow-ups. Cognitive, behavioral, and autism assessments were carried out with Griffith's scales or the Leiter-R, the Child Behavior Checklist, and the Child Autism Rating Scales 2. Multiple ANOVA 2 × 4 were run to outline behavioral phenotypic age-related syndromic markers and ANCOVA to value the weight of IQ and ASD-related traits on the psychopathological outcome. ResultsFindings showed that anxiety is a crucial phenotypic hallmark, independent of IQ but associated with autistic traits, that increases from infancy to adolescence in both CdLS and RSTS. Conclusion and implicationsBeing aware of the developmental challenges that growing children are called to face is essential for drawing up proper standards of assessment turning into target age-related interventions, ensuring these patients personalized healthcare and improvement in life quality.

An Endocrinological approach to Cornelia de Lange Syndrome

Cornelia de Lange syndrome is a developmental disorder with a great degree of clinical and genetical variability characterized by typical facial features, growth impairment and multi-organ anomalies. It is caused by mutations in the cohesin complex that is involved in regulation of gene expression. Growth disturbances are a major feature of the syndrome and have various underlying mechanisms. Other associations regarding endocrine function are represented by disturbances in the hypothalamic-pituitary axis, decreased bone density associated with fractures and genital malformations associated with menstrual irregularities and altered fertility.

CLINICAL CHARACTERISTICS IN CORNELIA DE LANGE SYNDROME OF THE FIRSTTYPE ON THEEXAMPLE OF A CLINICAL CASE

— Relevance: Cornelia de Lange syndrome is a rare congenital disorder associated with orphan diseases and is characterized by multiple stigmas of dysembryogenesis at birth. This syndrome occurs in newborns with a frequency of 1: 30,000 to 1: 10,000; there are no gender differences in the frequency of occurrence. Cornelia de Lange syndrome is a dominantly inherited disease, but most cases are sporadic de novo, therefore, mainly children with Cornelia de Lange syndrome are born from genetically healthy parents. Purpose: Using the example of a clinical case, to demonstrate the characteristic features of the clinical picture, namely the phenotype and deviations of the neurological status in Cornelia de Lange syndrome. Materials: Girl M., born in 2018, at the age of 1 year 11 months, together with her mother, was admitted to the Center for Pediatric Neurology and Medical Rehabilitation No. 2 in Tver, Russia. The girl had the following complaints (according to the mother): the child does not walk independently, stands with legs apart, and does not speak. She has obsessive movements ("crossed out" hand movement, waves her arms, puts his right hand behind the body, shakes objects in the mouth area), lags behind in development, does not differentiate significant adults, does not speak, there is no pointing gesture. Inpatient examination and treatment was carried out at the Center for Pediatric Neurology and Medical Rehabilitation. Results: Based on the examinations, the following diagnosis was established: Cornellia de Lange syndrome, type 1. Delayed physical, static-motor and mental development. Short stature. Congenital kidney anomaly: horseshoe kidney. Sensorineural hearing loss I-II degree The priority areas in this case are: improving the patient's quality of life, stimulating the development of the mental and motor spheres, socialization with other children. Conclusion: This clinical case demonstrates the need for early diagnosis of genetic disorders in order to build correct social and medical rehabilitation.

Generation of an induced pluripotent stem cell line SJTUXHi001-A from an autism spectrum disorder patient carrying a heterozygous mutation in HDAC8 (p.P359S)

Mutations in the HDAC8 are considered to be a prominent cause of Cornelia de Lange syndrome 5, a leading cause of intellectual disability and social disability. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from a 5-year-old girl diagnosed with autism spectrum disorder (ASD) who carries a heterozygous mutation in HDAC8 (c.1075C > T, p.Pro359Ser).

Two Nipped-B-Like Protein A (Nipbla) Gametologs in Chinese Tongue Sole (Cynoglossus semilaevis): The Identification of Alternative Splicing, Expression Pattern, and Promoter Activity Analysis

In mammals, the mutation of nipped-B-like protein (nipbl) leads to Cornelia de Lange Syndrome (CdLS), characterized by low birth weight, short stature, and structural abnormalities of the skeleton, heart, and gut. In Chinese tongue sole (Cynoglossus semilaevis), a typical marine fish exhibiting sexual size dimorphism, the nipbl homolog gene (nipped-B-like protein A (nipbla)) was also screened with female higher expression level by somatotropic and reproductive tissues’ transcriptomic analysis. In this study, two nipbla genes, namely, nipbla-w and nipbla-z, were identified from the W and Z chromosomes of C. semilaevis, respectively. Similar to other mammalian and fish species nipbl, the two homolog proteins of C. semilaevis contained two conserved domains, namely, cohesion_HEAT and Nipped-B_C. The phylogenetic tree analysis showed that these two nipbla gametolog proteins were first clustered together and then grouped with other fish species. At least two types of alternative splicing sites were observed in exon 12 of the nipbla-z gene, which produced nipbla-z-tv1 and nipbla-z-tv2. Also, the sex-biased expression patterns of different nipbla-w and nipbla-z transcripts in female and male tissues were revealed by quantitative PCR (qPCR). The highest expression level of nipbla-w was observed in female gonad. While nipbla-z-tv1 exhibited relatively high expression in the muscle, liver, gonad, and brain, nipbla-z-tv2 only showed its expression superiority in the muscle of male individuals. The promoter regions of nipbla genes were amplified, and their transcription activity was successfully verified by a dual-luciferase reporter system. After nipbla-w and nipbla-z knockdown in the brain cell lines by RNA interference, a series of growth-related genes were influenced, including Bone Morphogenetic Protein 4 (bmp4), Wnt Family Member 11 (wnt11), and Sprouty Related EVH1 Domain Containing 2 (spred2). The prediction of transcription factors suggested that c-Jun, sex-determining region Y (SRY), POU Class 1 Homeobox 1 (POU1F1a), myogenic differentiation antigen (MyoD), signal transducer and activator of transcription 5a (STAT5A), and nuclear factor I C (Nfic) might be the putative upstream regulatory factors for nipbla; among them, c-Jun has been verified to effectively regulate the transcriptional activity of nipbla. The identification of two nipbla genes provided important data for interpreting the sexual size dimorphism in C. semilaevis.

A case of Mounier-Kuhn syndrome in a geriatric patient

Mounier-Kuhn syndrome, or tracheobronchomegaly, is a rare clinical and radiologic condition characterized by marked tracheobronchial dilation and recurrent lower respiratory tract infections. The syndrome was first described by Mounier-Kuhn in 1932, and few cases have been reported in the medical literature [1]. The clinical presentation varies widely, from asymptomatic disease with preserved lung functions to recurrent chest infections, exertional dyspnoea to even respiratory failure in severe cases. Diagnosis is often made by using CT, through which abnormally large air passages are detected. In adults, the diagnostic criteria are diameters of the trachea &gt;30 mm, right main bronchus &gt;20 mm and of the left main bronchus &gt;18 mm [2-4]. Upon pulmonary function testing, decreased bronchial flow speed, increased tidal volume, and dead spaces may be observed. Bronchoscopy can detect the pathologic processes that affect the tracheobronchial structures. Connective-tissue diseases, ataxia-telangiectasia, ankylosing spondylitis, EhlersDanlos syndrome, Marfan syndrome, Kenny-Caffey syndrome, Brachmann-de Lange syndrome, and cutis laxa (elastolysis) are also associated with secondary tracheobronchial enlargement [2-5]. All these conditions should be considered in the differential diagnosis.