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Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach.

ABSTRACT: Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS therapeutic approaches.

SUBMITTER: Sarogni P

PROVIDER: S-EPMC7231464 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach.

Sarogni Patrizia P Pallotta Maria M MM Musio Antonio A

Journal of medical genetics 20191108 5

Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS ...[more]

PMID: 31704779

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Mutational Screening and Prenatal Diagnosis in Cornelia de Lange syndrome.

Project description:Phenotypic variability and the lack of a diagnostic marker have complicated the rapid diagnosis and genetic counseling for Cornelia de Lange syndrome (CdLS). The clinical features of CdLS are striking and easily recognizable by characteristic facial dysmorphism, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities with severe mental retardation. The molecular diagnosis is essential for predicting prognosis and genetic counseling in the affected family, especially while planning the next pregnancy. We report here from India six cases of CdLS and how precise mutational screening in two cases helped in prenatal diagnosis and proved significant in prevention of recurrence in the affected family.

| S-EPMC3931894 | biostudies-literature

On the molecular etiology of Cornelia de Lange syndrome.

Project description:Cornelia de Lange syndrome (CdLS) is genetically heterogeneous and is usually sporadic, occurring approximately once per 10,000 births. CdLS individuals display diverse and variable deficits in growth, mental development, limbs, and organs. In the past few years it has been shown that CdLS is caused by gene mutations affecting proteins involved in sister chromatid cohesion. Studies in model organisms, and more recently in human cells, have revealed, somewhat unexpectedly, that the developmental deficits in CdLS likely arise from changes in gene expression. The mechanisms by which cohesion factors regulate gene expression remain to be elucidated, but current data suggest that they likely regulate transcription in multiple ways.

| S-EPMC2733214 | biostudies-literature

Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome.

Project description:Cornelia 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.

| S-EPMC7889653 | biostudies-literature

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Project description:Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

| S-EPMC7136165 | biostudies-literature

Cornelia de Lange syndrome in diverse populations.

Project description:Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37?years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

| S-EPMC6367950 | biostudies-literature

Cornelia de Lange syndrome, cohesin, and beyond.

Project description:Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-strand DNA break repair and long-range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed 'cohesinopathies'), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS-related proteins.

| S-EPMC2853897 | biostudies-literature

Cornelia de Lange Syndrome as Paradigm of Chromatinopathies.

Project description:Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.

| S-EPMC8603810 | biostudies-literature

Transcriptome comparison between CHOPS syndrome and Cornelia de Lange syndrome

Project description:CHOPS syndrome is caused by germline gain-of-function mutations of AFF4. Cornelia de Lange syndrome is caused by germline mutations of cohesin loading factors or cohesin complex genes such as NIPBL, SMC1A, SMC3 and HDAC8. There are many overlapping clinical features exist between CHOPS syndrome and Cornelia de Lange syndrome. To identified commonly dysregulated genes in CHOPS syndrome and Cornelia de Lange syndrome, we perfomred side-by-side transcriptome comparison between CHOPS syndrome and Cornelia de Lange syndrome.

2015-01-27 | GSE64034 | GEO

Successful Growth Hormone Therapy in Cornelia de Lange Syndrome.

Project description:Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS.

| S-EPMC5785645 | biostudies-literature

Temporal bone CT findings in Cornelia de Lange syndrome.

Project description:Background and purposeCornelia de Lange syndrome is a rare developmental malformation syndrome with a high prevalence of hearing impairment. The purposes of this study were to describe the characteristic temporal bone CT findings in patients with Cornelia de Lange syndrome and to correlate audiometric data with radiologic findings in these patients.Materials and methodsTen children (6 girls and 4 boys; mean age, 42.0 months) who were clinically diagnosed with Cornelia de Lange syndrome (classic, n = 5; mild form, n = 5) were enrolled. Temporal bone CT was prospectively performed, and 32 aspects of each temporal bone CT were analyzed, 21 by direct measurement and 11 by visual inspection. Twenty age-matched children (n = 20 ears) with normal temporal bone CT scans served as a control group. Audiologic tests were also performed on all patients.ResultsCharacteristic temporal bone CT findings of Cornelia de Lange syndrome were external auditory canal stenosis, soft-tissue opacification of the hypoplastic tympanomastoid cavity, dysmorphic ossicle, hypoplastic cochlea, and dysplastic vestibule, all of which were more prevalent in patients with the classic form of the disease than in those with the mild form. Children who had more severe structural abnormalities on temporal bone CT had worse hearing levels compared with those without structural abnormalities.ConclusionTemporal bone CT scans in Cornelia de Lange syndrome could document combined structural abnormalities of the external, middle, and inner ear, which were one of the characteristic clinical manifestations; CT abnormalities were well correlated with the audiometric data.

| S-EPMC8118888 | biostudies-literature

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