Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency

INTRODUCTION: This study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB). METHODS: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed. RESULTS: The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group. CONCLUSION: This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management

The detection of a strong episignature for Chung–Jansen syndrome, partially overlapping with Börjeson–Forssman–Lehmann and White–Kernohan syndromes

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung–Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung–Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White–Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson–Forssman–Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung–Jansen, Börjeson–Forssman–Lehmann and White–Kernohan syndromes.</p

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Comment améliorer l’adhésion aux soins des adolescents suicidants après une prise en charge aux urgences : une revue de la littérature

International audienceOBJECTIVES:Suicidal adolescents admitted in an Emergency Department (ED) present a high risk of suicidal reattempts. Poor observance of follow-up in this particular group imped the efficacity of the treatment. We propose to summarize the international literature on ED interventions promoting suicidal adolescents' adherence to care. METHOD:We carried out a comprehensive review of papers listed in PubMed, PsycInfo, and CINHAL databases using keywords about adolescence, suicide, and ED. We also manually consulted the main journals specialized in suicidology (Crisis and Suicide and Life-Threatening Behavior) and adolescence (Journal of the American Academy of Child and Adolescent Psychiatry, Journal of Adolescent Health, Neuropsychiatrie de l'Enfance et de l'Adolescence). We selected the relevant articles describing or evaluating one or more interventions initiated in the ED and designed to promote adolescent adherence to post-emergency care. The results are presented in a narrative review form. RESULTS:Interventions are organized in three groups: interventions that take place solely at the ED (problem-solving interventions and educational interventions directed to families) and interventions that take place during and after emergency care (we included in this group the ED-Care program, the FISP program, and the SAFETY program), to which should be added interventions that take place prior to care, in particular specific trainings for medical and paramedical teams. Small samples and barriers in measuring adherence to care make statistical comparisons difficult, yet the interventions that seem most effective are those that target the time both during and after ED discharge, those which are implemented most rapidly after discharge, those which actively include parents, and those which involve an implication of the families about barriers to follow-up. CONCLUSION:Our results show an effectiveness of complete programs on short-term compliance but no conclusion can be drawn on long-term effects. Most comprehensive care programs are based on the principle of adolescent compliance, which remains problematic. Until today, no ideal protocol exists to improve short-term as well as long-term compliance to care among adolescents after a suicide attempt. We have to improve our understanding of facilitators and barriers to follow-up using quantitative as well as qualitative research studies. Although it is well established that parents' involvement in the early stages of care is essential, little is known about the underlying processes. In these situations, qualitative studies could help to better target interventions that lead more particularly to follow up compliance in adolescence

Supportive effect of body contact care with ylang ylang aromatherapy and mobile intervention team for suicide prevention: A pilot study.

To assess understudied, alternative suicide prevention modalities in a mental health care setting. This was a prospective study of patients (n = 140, 68 cases and 72 controls) who were admitted to hospital or who contacted an SOS suicide crisis line for suicidal ideation or attempts. Psychiatric diagnoses (Mini-International Neuropsychiatric Interview) and intensity of anxiety/depression/suicidality (Hamilton Anxiety Rating Scale, Montgomery-Åsberg Depression Rating Scale, and Beck Scale for Suicidal Ideation) were assessed. All intervention group subjects received a crisis card with a crisis line number, interviews with psychologists or volunteers and a telephone call on days 10 to 21, then 6 months later. These subjects also had a choice between two further 4-month interventions: body contact care or mobile intervention team visits. The interventions significantly reduced the number of suicide attempts and suicide (3%) at 6 months compared with the control condition (12%). There were fewer losses to follow-up in the intervention group (7.35%) than in the control group (9.72%). The results favour the implementation of integrated care and maintaining contact in suicide prevention

Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

Abstract: Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease