22 research outputs found
P315: Novel variants in the CACNA1B gene: A case presentation of neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements
P134: Neuronal pathways by differential tractography correlate with clinical outcomes following gene therapy for GM1 gangliosidosis: New biomarker for neurodegenerative diseases*
DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature.
Two patients diagnosed with DYRK1A Syndrome in the Undiagnosed Diseases Program with ophthalmologic abnormalities not previously described
CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism
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Kilquist syndrome: A novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2.
Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next-generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared with control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with the described phenotype of the Slc12a2-knockout mouse model, our results suggest that the absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues
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Kilquist Syndrome: A Novel Syndromic Hearing Loss Disorder Caused by Homozygous Deletion of SLC12A2.
Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next-generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared with control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with the described phenotype of the Slc12a2-knockout mouse model, our results suggest that the absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues
Disordered Eating and Food Restrictions in Children with PANDAS/PANS
Objective: Sudden onset clinically significant eating restrictions are a defining feature of the clinical presentation of some of the cases of pediatric acute-onset neuropsychiatric syndrome (PANS). Restrictions in food intake are typically fueled by contamination fears; fears of choking, vomiting, or swallowing; and/or sensory issues, such as texture, taste, or olfactory concerns. However, body image distortions may also be present. We investigate the clinical presentation of PANS disordered eating and compare it with that of other eating disorders. Methods: We describe 29 patients who met diagnostic criteria for PANS. Most also exhibited evidence that the symptoms might be sequelae of infections with Group A streptococcal bacteria (the pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections [PANDAS] subgroup of PANS). Results: The clinical presentations are remarkable for a male predominance (2:1 M:F), young age of the affected children (mean=9 years; range 5–12 years), acuity of symptom onset, and comorbid neuropsychiatric symptoms. Conclusions: The food refusal associated with PANS is compared with symptoms listed for the new Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V) diagnosis of avoidant/restrictive food intake disorder (ARFID). Treatment implications are discussed, as well as directions for further research
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Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.
Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis
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Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.
Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis
De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals. </p