Assessing the clinical utility of protein structural analysis in genomic variant classification: experiences from a diagnostic laboratory

Genome Medicine, Год журнала: 2022, Номер 14(1)

Опубликована: Июль 22, 2022

The widespread clinical application of genome-wide sequencing has resulted in many new diagnoses for rare genetic conditions, but testing regularly identifies variants uncertain significance (VUS). remarkable rise the amount genomic data been paralleled by a number protein structures that are now publicly available, which may have utility interpretation missense and in-frame insertions or deletions. Within UK National Health Service medicine diagnostic laboratory, we investigated VUS over 5-year period were evaluated using structural analysis how often this aided variant classification. We found 99 novel across 67 genes initially classified as our laboratory standard classification guidelines further structure was requested. Evidence from used re-assessment 64 variants, 47 subsequently reclassified pathogenic likely 17 remained VUS. identified several case studies where predicting disease mechanisms consistent with observed phenotypes, including loss-of-function through thermodynamic destabilisation disruption ligand binding, gain-of-function de-repression escape proteasomal degradation. shown silico can aid give insights into pathogenicity. Based on experience, propose generic evidence-based workflow incorporating information practice to facilitate

Язык: Английский

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Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL

Neurology, Год журнала: 2022, Номер 99(5)

Опубликована: Май 31, 2022

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering variant in 1 of the 34 epidermal growth factor-like repeat (EGFR) domains NOTCH3 protein. CADASIL has variable phenotypic presentation,

Язык: Английский

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Characterizing and explaining the impact of disease-associated mutations in proteins without known structures or structural homologs

Briefings in Bioinformatics, Год журнала: 2022, Номер 23(4)

Опубликована: Апрель 27, 2022

Mutations in human proteins lead to diseases. The structure of these can help understand the mechanism such diseases and develop therapeutics against them. With improved deep learning techniques, as RoseTTAFold AlphaFold, we predict even absence structural homologs. We modeled extracted domains from 553 disease-associated without known protein structures or close homologs Protein Databank. noticed that model quality was higher Root mean square deviation (RMSD) lower between AlphaFold models for could be assigned CATH families compared those which only Pfam unknown not either. predicted ligand-binding sites, protein-protein interfaces conserved residues structures. then explored whether missense mutations were proximity functional they destabilized based on ddG calculations pathogenic. explain 80% destabilization pathogenicity. When polymorphisms, a larger percentage buried, closer destabilizing Usage two state-of-the-art techniques provide better confidence our predictions, 93 additional explained solely models.

Язык: Английский

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GABRG2 Variants Associated with Febrile Seizures

Biomolecules, Год журнала: 2023, Номер 13(3), С. 414 - 414

Опубликована: Фев. 22, 2023

Febrile seizures (FS) are the most common form of epilepsy in children between six months and five years age. FS is a self-limited type fever-related seizure. However, complicated prolonged can lead to complex partial epilepsy. We found that among GABAA receptor subunit (GABR) genes, variants associated with harbored γ2 (GABRG2). Here, we characterized effects eight on biogenesis channel function. Two-thirds GABRG2 followed expected autosomal dominant inheritance occurred as missense nonsense variants. The remaining one-third appeared de novo affected probands only loss function negative effect likely caused phenotype. In general, result broad spectrum phenotypic severity, ranging from asymptomatic, FS, genetic febrile plus (GEFS+), Dravet syndrome individuals. data presented here support link epilepsy, variants, shedding light relationship variant topological occurrence disease severity.

Язык: Английский

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SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis

Brain, Год журнала: 2023, Номер 146(12), С. 5198 - 5208

Опубликована: Авг. 29, 2023

Abstract Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand mechanism and improve therapeutic decision-making. We aggregated genetic clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) functional for 184 (14.1% lp/p). Clinical were available subset of 126 individuals. explored potential variant positions on GAT1 3D structure pathogenicity, altered molecular function phenotype severity using bioinformatic approaches. The transmembrane domains 1, 6 extracellular loop 4 (EL4) enriched patient over population variants. Across functionally tested missense (n = 156), spatial proximity ligand was associated loss-of-function transporter activity. For complete loss vitro GABA uptake, we found 4.6-fold enrichment patients having severe versus non-severe (P 2.9 × 10−3, 95% confidence interval: 1.5–15.3). In summary, delineated between SLC6A1-related disorders. This knowledge supports biology-informed interpretation research All our be interactively portal (https://slc6a1-portal.broadinstitute.org/).

Язык: Английский

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