{"doi":"10.1016/j.ymgme.2022.03.007","title":"Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay","abstract":"We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C. This gene has not previously been associated with a Mendelian disease, and based on the population database, gnomAD, the gene has a low tolerance for loss-of-function variants (pLI = 1, o/e = 0.07). We functionally evaluated the PPP5C variant in C. elegans by knocking the variant into the orthologous gene, pph-5, at the corresponding residue, Ala48Thr. We employed assays in three different biological processes where pph-5 was known to function through opposing the activity of genes, mec-15 and sep-1. We demonstrated that, in contrast to control animals, the pph-5 Ala48Thr variant suppresses the neurite growth phenotype and the GABA signaling defects of mec-15 mutants, and the embryonic lethality of sep-1 mutants. The Ala48Thr variant did not display dominance and behaved similarly to the reference pph-5 null, indicating that the variant is likely a strong hypomorph or complete loss-of-function. We conclude that pph-5 Ala48Thr is damaging in C. elegans. By extension in the proband, PPP5C p.Ala47Thr is likely damaging, the de novo dominant presentation is consistent with haplo-insufficiency, and the PPP5C variant is likely responsible for one or more of the proband's phenotypes.","journal":"Molecular Genetics and Metabolism","year":2022,"id":261860,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":15091,"name":"Jill A. Rosenfeld","orcid":"0000-0001-5664-7987","position":1,"is_corresponding":false},{"id":249404,"name":"Lindsay C. Burrage","orcid":"0000-0002-5108-8861","position":2,"is_corresponding":false},{"id":308535,"name":"Lisa Emrick","orcid":"0000-0002-4844-9056","position":3,"is_corresponding":false},{"id":354473,"name":"Seema R. Lalani","orcid":"0000-0003-0707-657X","position":4,"is_corresponding":false},{"id":917123,"name":"Ruben Attali","orcid":null,"position":5,"is_corresponding":false},{"id":203840,"name":"Joshua N. Bembenek","orcid":"0000-0002-0966-2268","position":6,"is_corresponding":false},{"id":519156,"name":"Hieu D. Hoang","orcid":"0000-0002-5893-7651","position":7,"is_corresponding":false},{"id":274077,"name":"Dustin Baldridge","orcid":"0000-0002-6027-6020","position":8,"is_corresponding":false},{"id":369000,"name":"Gary A. Silverman","orcid":"0000-0002-2686-2843","position":9,"is_corresponding":false},{"id":246656,"name":"Tim Schedl","orcid":"0000-0003-2148-2996","position":10,"is_corresponding":false},{"id":485359,"name":"Stephen C. Pak","orcid":"0000-0002-8089-3237","position":11,"is_corresponding":false},{"id":800856,"name":"Sara M. Fielder","orcid":"0000-0001-6008-4689","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:26:16.663144Z","pmid":"35361529","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}