Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.Grant support for L. Boyle provided by TL1TR001875.info:eu-repo/semantics/publishedVersio

<i>USP27X </i>variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p

<i>USP27X </i>variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p

USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature

A rare homozygous missense GDF2 (BMP9) mutation causing PAH in siblings: Does BMP10 status contribute?

Pulmonary arterial hypertension (PAH) is a disease characterized by pathological remodeling of the pulmonary vasculature causing elevated pulmonary artery pressures and ultimately, right ventricular failure from chronic pressure overload. Heterozygous pathogenic GDF2 (encoding bone morphogenetic protein 9 (BMP9)) variants account for some (>1%) adult PAH cases. Only three pediatric PAH cases, harboring homozygous or compound heterozygous variants, are reported to date. Ultra-rare pathogenic GDF2 variants are reported in hereditary hemorrhagic telangiectasia and overlapping disorders characterized by telangiectasias and arteriovenous malformations (AVMs). Here, we present two siblings with PAH homozygous for a GDF2 mutation that impairs BMP9 proprotein processing and reduces growth factor domain availability. We confirm an absence of measurable plasma BMP9 whereas BMP10 levels are detectable and serum-dependent endothelial BMP activity is evident. This contrasts with the absence of activity which we reported in two children with homozygous pathogenic GDF2 nonsense variants, one with PAH and one with pulmonary AVMs, both with telangiectasias, suggesting loss of BMP10 and endothelial BMP activity in the latter may precipitate telangiectasia development. An absence of phenotype in related heterozygous GDF2 variant carriers suggests incomplete penetrance in PAH and AVM-related diseases, indicating that additional somatic and/or genetic modifiers may be necessary for disease precipitation

A rare homozygous missense GDF2 ( BMP9 ) mutation causing PAH in siblings: Does BMP10 status contribute?

Abstract: Pulmonary arterial hypertension (PAH) is a disease characterized by pathological remodeling of the pulmonary vasculature causing elevated pulmonary artery pressures and ultimately, right ventricular failure from chronic pressure overload. Heterozygous pathogenic GDF2 (encoding bone morphogenetic protein 9 (BMP9)) variants account for some (>1%) adult PAH cases. Only three pediatric PAH cases, harboring homozygous or compound heterozygous variants, are reported to date. Ultra‐rare pathogenic GDF2 variants are reported in hereditary hemorrhagic telangiectasia and overlapping disorders characterized by telangiectasias and arteriovenous malformations (AVMs). Here, we present two siblings with PAH homozygous for a GDF2 mutation that impairs BMP9 proprotein processing and reduces growth factor domain availability. We confirm an absence of measurable plasma BMP9 whereas BMP10 levels are detectable and serum‐dependent endothelial BMP activity is evident. This contrasts with the absence of activity which we reported in two children with homozygous pathogenic GDF2 nonsense variants, one with PAH and one with pulmonary AVMs, both with telangiectasias, suggesting loss of BMP10 and endothelial BMP activity in the latter may precipitate telangiectasia development. An absence of phenotype in related heterozygous GDF2 variant carriers suggests incomplete penetrance in PAH and AVM‐related diseases, indicating that additional somatic and/or genetic modifiers may be necessary for disease precipitation

Prenatal Genetic Testing in the Era of Next Generation Sequencing: A One-Center Canadian Experience

The introduction of next generation sequencing (NGS) technologies has revolutionized the practice of Medical Genetics, and despite initial reticence in its application to prenatal genetics (PG), it is becoming gradually routine, subject to availability. Guidance for the clinical implementation of NGS in PG, in particular whole exome sequencing (ES), has been provided by several professional societies with multiple clinical studies quoting a wide range of testing yields. ES was introduced in our tertiary care center in 2017; however, its use in relation to prenatally assessed cases has been limited to the postnatal period. In this study, we review our approach to prenatal testing including the use of microarray (CMA), and NGS technology (gene panels, ES) over a period of three years. The overall diagnostic yield was 30.4%, with 43.2% of those diagnoses being obtained through CMA, and the majority by using NGS technology (42% through gene panels and 16.6% by ES testing, respectively). Of these, 43.4% of the diagnoses were obtained during ongoing pregnancies. Seventy percent of the abnormal pregnancies tested went undiagnosed. We are providing a contemporary, one tertiary care center retrospective view of a real-life PG practice in the context of an evolving use of NGS within a Canadian public health care system that may apply to many similar jurisdictions around the world

ANKRD26-related thrombocytopenia and myeloid malignancies

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