Dataset Information

Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants.

ABSTRACT: Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms because they may result in markedly different clinical phenotypes. Here, we generated an extensive database of documented germline GOF and LOF pathogenic variants by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various gene- and protein-level features of GOF and LOF variants and applied machine learning and statistical analyses to identify discriminative features. We found that GOF variants were enriched in essential genes, for autosomal-dominant inheritance, and in protein binding and interaction domains, whereas LOF variants were enriched in singleton genes, for protein-truncating variants, and in protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a broad set of annotated features and downloading of up-to-date versions. These results improve our understanding of how variants affect gene/protein function and may ultimately guide future treatment options.

SUBMITTER: Sevim Bayrak C

PROVIDER: S-EPMC8715146 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants.

Sevim Bayrak Cigdem C Stein David D Jain Aayushee A Chaudhary Kumardeep K Nadkarni Girish N GN Van Vleck Tielman T TT Puel Anne A Boisson-Dupuis Stephanie S Okada Satoshi S Stenson Peter D PD Cooper David N DN Schlessinger Avner A Itan Yuval Y

American journal of human genetics 20211110 12

Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms because they may result in markedly different clinical phenotypes. Here, we generated an extensive database of documented germline GOF and LOF pathogenic variants by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then ...[more]

PMID: 34762822

Similar Datasets

Project description:AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants.

Dataset Information

Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants.

Publications

Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets