Taxonomic review of the genus Stenotus Jakovlev (Hemiptera: Heteroptera: Miridae) from the Korean Peninsula

AbstractA genus Stenotus Jakovlev (Hemiptera: Heteroptera: Miridae) is reviewed taxonomically from the Korean Peninsula with a new record Stenotus binotatus (Fabricius 1794). Morphological information, such as descriptions of male and female genitalia, of the Korean species with photographs and illustrations, and a key to the Korean species are provided

Genome-wide DNA methylation analysis in cohesin mutant human cell lines

The cohesin complex has recently been shown to be a key regulator of eukaryotic gene expression, although the mechanisms by which it exerts its effects are poorly understood. We have undertaken a genome-wide analysis of DNA methylation in cohesin-deficient cell lines from probands with Cornelia de Lange syndrome (CdLS). Heterozygous mutations in NIPBL, SMC1A and SMC3 genes account for ∼65% of individuals with CdLS. SMC1A and SMC3 are subunits of the cohesin complex that controls sister chromatid cohesion, whereas NIPBL facilitates cohesin loading and unloading. We have examined the methylation status of 27 578 CpG dinucleotides in 72 CdLS and control samples. We have documented the DNA methylation pattern in human lymphoblastoid cell lines (LCLs) as well as identified specific differential DNA methylation in CdLS. Subgroups of CdLS probands and controls can be classified using selected CpG loci. The X chromosome was also found to have a unique DNA methylation pattern in CdLS. Cohesin preferentially binds to hypo-methylated DNA in control LCLs, whereas the differential DNA methylation alters cohesin binding in CdLS. Our results suggest that in addition to DNA methylation multiple mechanisms may be involved in transcriptional regulation in human cells and in the resultant gene misexpression in CdLS

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population

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

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

Facial Diagnosis of Mild and Variant CdLS: Insights from a Dysmorphologist Survey

Cornelia de Lange syndrome (CdLS) is a dominant disorder with classic severe forms and milder atypical variants. Central to making the diagnosis is identification of diagnostic facial features. With the recognition that patients with SMC1A and SMC3 mutations have milder, atypical features, we surveyed 65 dysmorphologists using facial photographs from 32 CdLS patients with the goals of (1) Illustrating examples of milder patients with SMC1A mutations and (2) Obtaining objective data to determine which facial features were useful and misleading in making a diagnosis of CdLS. Clinicians were surveyed whether the patient had CdLS or another diagnosis, the certainty of response and the clinical features used to support each response. Using only facial photographs, an average of 24 cases (75%) were accurately diagnosed per clinician. Correct diagnoses were made in 90% of classic CdLS and 87% of non-CdLS cases, however, only 54% of mild or variant CdLS were correctly diagnosed by respondents. We confirmed that CdLS is most accurately diagnosed in childhood and the diagnosis becomes increasingly difficult with age. This survey demonstrated that emphasis is placed on the eyebrows, nasal features, prominent upper lip and micrognathia. In addition, the presence of fuller, atypical eyebrows, a prominent nasal bridge and significant prognathism with age dissuaded survey takers from arriving at a diagnosis of CdLS in individuals with mild NIPBL and SMC1A mutations. This work underscores the difficulty in diagnosing patients with mild and variant CdLS and serves to objectively classify both useful and misleading features in the diagnosis of CdLS

NIPBL Mutational Analysis in 120 Individuals with Cornelia de Lange Syndrome and Evaluation of Genotype-Phenotype Correlations

The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations

Pediatric joint hypermobility: a diagnostic framework and narrative review

Abstract Background Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. Observations The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers–Danlos syndrome at any age. Conclusions This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population

Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.status: publishe

Cornelia de Lange syndrome: further delineation of phenotype, cohesin biology and educational focus, 5th Biennial Scientific and Educational Symposium abstracts.

Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers, professionals, and schools. The following abstracts are presentations from the 5th Cornelia de Lange Syndrome Scientific and Educational Symposium on June 20-21, 2012, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting, Lincolnshire, IL. The research committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts and subsequently disseminates the information to the families. In addition to the basic science and clinical discussions, there were educationally-focused talks related to practical aspects of management at home and in school. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD

Cornelia de Lange syndrome: further delineation of phenotype, cohesin biology and educational focus, 5th Biennial Scientific and Educational Symposium abstracts.

Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers, professionals, and schools. The following abstracts are presentations from the 5th Cornelia de Lange Syndrome Scientific and Educational Symposium on June 20-21, 2012, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting, Lincolnshire, IL. The research committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts and subsequently disseminates the information to the families. In addition to the basic science and clinical discussions, there were educationally-focused talks related to practical aspects of management at home and in school. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD