New genes involved in Angelman syndrome-like: Expanding the genetic spectrum

Aguilera, Cinthia; Gabau, Elisabeth; Ramirez-Mallafré, Ariadna; Gasca, Carme Brun i; Domínguez‐Carral, Jana; Delgadillo, Veronica; Laurie, Steve; Derdak, Sophia; Padilla, Natàlia; Cruz, Xavier de la; Capdevila, Núria; Spataro, Nino; Baena, Neus; Guitart, Míriam; Ruiz, Anna

doi:10.1371/journal.pone.0258766

Cited by 13 publications

(10 citation statements)

References 60 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings pave the way for future studies aiming at further deciphering the mechanisms regulated by this stress-responsive pathway for the understanding of neurodevelopmental deficiency observed in NDDs. In support of our findings, the recent reporting of a deleterious de novo mutation of the HSF2 gene linked to Angelman Syndrome 70 is a further proof of the importance of the integrity of the HSF2 pathway in neurodevelopment contexts.…”

Section: Discussion (See Also Supplementary Discussion)supporting

confidence: 89%

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

et al. 2022

View full text Add to dashboard Cite

Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

show abstract

Section: Discussion (See Also Supplementary Discussion)supporting

confidence: 89%

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In the four isoUsage modules we highlight here, isoform-level information is critical in refining interpretations of the cellular mechanisms contributing to disease during brain development. For example, while the BAF complex is already known to be involved in neural development and has been implicated in ASD (65,66), our analysis revealed that specific exon combinations and consequently protein domains are altered between modules driving different cellular processes. In another example, isoform-level analysis identified a novel 3'UTR sequence in ELAVL1 which is conserved specifically in primates and human.…”

Section: Network Context Of Developmental Isoform Regulationmentioning

confidence: 81%

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Patowary

Zhang

Jops

et al. 2023

Preprint

View full text Add to dashboard Cite

Human brain development is under tight molecular genetic control and the recent advent of single-cell genomics has revolutionized our ability to elucidate the diverse underlying cell-types and states. Although RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders, previous work has not systematically investigated the role of cell-type-specific splicing or transcript-isoform diversity during human brain development. Here, we leverage single molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone (GZ) and cortical plate (CP) regions of the developing human neocortex at tissue and single-cell resolution. We identify 214,516 unique isoforms, corresponding to 22,391 genes. Remarkably, we find that 72.6% of these are novel and together with >7,000 novel-spliced exons expands the proteome by 92,422 proteoforms. We uncover myriad novel isoform switches during cortical neurogenesis, implicating previously-uncharacterized RNA-binding protein-mediated and other regulatory mechanisms in cellular identity and disease. Early-stage excitatory neurons exhibit the greatest isoform diversity and isoform-based single-cell clustering identifies previously uncharacterized cell states. Leveraging this resource, we re-prioritize thousands of rare de novo risk variants associated with neurodevelopmental disorders (NDDs) and reveal that risk genes are strongly associated with the number of unique isoforms observed per gene. Altogether, this work uncovers a substantial contribution of transcript-isoform diversity in cellular identity in the developing neocortex, elucidates novel genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders, and provides a comprehensive isoform-centric gene annotation for the developing human brain.

show abstract

“…Three variants have been previously reported in the literature. 10 , 14 , 22 , 23 Eight of 14 patients had frameshift variants. Five of 8 frameshift variants led to protein truncation (nonsense).…”

Section: Resultsmentioning

confidence: 99%

Adult Phenotype of SYNGAP1 -DEE

Rong,

Benke,

Zulfiqar Ali

et al. 2023

Neurol Genet

View full text Add to dashboard Cite

Background and ObjectivesSYNGAP1variants are associated with rare developmental and epileptic encephalopathies (DEEs). AlthoughSYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults withSYNGAP1variants and epilepsy.MethodsPatients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P)SYNGAP1variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden.ResultsFourteen unrelated adult patients (median: 21 years, range: 18–65 years) withSYNGAP1-DEE were identified, 11 with novel and 3 with known LP/PSYNGAP1de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger.DiscussionSeventy-one percent of patients withSYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults withSYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.

show abstract

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum

Cited by 13 publications

References 60 publications

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Adult Phenotype of SYNGAP1 -DEE

Contact Info

Product

Resources

About