Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.

{"sci_version": "1.0", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:21865298", "kind": "science-record", "revision": 2, "content_hash": "sha256:9639b77cc8df59a6efd59761163bbe597ebcceaa9cebc1fd31ad3ef5bbacf4aa", "created_at": "2026-11-01T15:40:01Z", "updated_at": "2026-11-01T18:46:49Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.", "doi": "10.1093/hmg/ddr363", "pmid": "21865298", "authors": ["Patricia B S Celestino-Soper", "Chad A Shaw", "Stephan J Sanders", "Jian Li", "Michael T Murtha", "A Gulhan Ercan-Sencicek", "Lea Davis", "Susanne Thomson", "Tomasz Gambin", "A Craig Chinault", "Zhishuo Ou", "Jennifer R German", "Aleksandar Milosavljevic", "James S Sutcliffe", "Edwin H Cook", "Pawel Stankiewicz", "Matthew W State", "Arthur L Beaudet"], "journal": "Human molecular genetics", "year": 2011, "abstract": "Autism is a neurodevelopmental disorder with increasing evidence of heterogeneous genetic etiology including de novo and inherited copy number variants (CNVs). We performed array comparative genomic hybridization using a custom Agilent 1 M oligonucleotide array intended to cover 197 332 unique exons in RefSeq genes; 98% were covered by at least one probe and 95% were covered by three or more probes with the focus on detecting relatively small CNVs that would implicate a single protein-coding gene. The study group included 99 trios from the Simons Simplex Collection. The analysis identified and validated 55 potentially pathogenic CNVs, categorized as de novo autosomal heterozygous, inherited homozygous autosomal, complex autosomal and hemizygous deletions on the X chromosome of probands. Twenty percent (11 of 55) of these CNV calls were rare when compared with the Database of Genomic Variants. Thirty-six percent (20 of 55) of the CNVs were also detected in the same samples in an independent analysis using the 1 M Illumina single-nucleotide polymorphism array. Findings of note included a common and sometimes homozygous 61 bp exonic deletion in SLC38A10, three CNVs found in lymphoblast-derived DNA but not present in whole-blood derived DNA and, most importantly, in a male proband, an exonic deletion of the TMLHE (trimethyllysine hydroxylase epsilon) that encodes the first enzyme in the biosynthesis of carnitine. Data for CNVs present in lymphoblasts but absent in fresh blood DNA suggest that these represent clonal outgrowth of individual B cells with pre-existing somatic mutations rather than artifacts arising in cell culture. GEO accession number GSE23765 (http://www.ncbi.nlm.nih.gov/geo/, date last accessed on 30 August 2011). Genboree accession: http://genboree.org/java-bin/gbrowser.jsp?refSeqId=1868&entryPointId=chr17&from=53496072&to=53694382&isPublic=yes, date last accessed on 30 August 2011.", "claims": [{"id": "claim-target-result", "statement": "The study identified and validated 55 potentially pathogenic CNVs; the abstract does not specify a statistical method, but provides the source-data route through GEO accession number GSE23765 and a Genboree accession.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:21865298", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "The analysis identified and validated 55 potentially pathogenic CNVs, categorized as de novo autosomal heterozygous, inherited homozygous autosomal, complex autosomal and hemizygous deletions on the X chromosome of probands."}, {"asset": "source:pmid:21865298", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "GEO accession number GSE23765 (http://www.ncbi.nlm.nih.gov/geo/, date last accessed on 30 August 2011)."}, {"asset": "source:pmid:21865298", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Genboree accession: http://genboree.org/java-bin/gbrowser.jsp?refSeqId=1868&entryPointId=chr17&from=53496072&to=53694382&isPublic=yes, date last accessed on 30 August 2011."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The study identified and validated 55 potentially pathogenic CNVs; the abstract does not specify a statistical method, but provides the source-data route through GEO accession number GSE23765 and a Genboree accession.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:21865298"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:21865298", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1093/hmg/ddr363", "sha256": "sha256:e590f9ebccc8f2dca605a3b32a9ce8efe59bba8f47974f089204f59c56038e72", "bytes": 1941, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1093/hmg/ddr363", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC3196886", "source": "ncbi_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}], "gaps": []}, "analysis": {"state": "absent", "methods": [], "targets": [], "gaps": ["method", "operations"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"tier": "R4", "expressible": false, "required_operations": [], "missing_operations": [], "basis": "The reader quoted the method the paper names (not named), but the corpus's method extractor could not map it onto a DSL operation, so the method is published but not expressible."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R4", "reachable": false, "accessions": [], "resolved_accessions": [], "statements": [], "basis": "The paper names no accession to its source data, so the data has to come from the authors."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:21865298"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:21:06Z", "independence": "single_reader"}, "evidence_check": {"method": null, "availability": null}, "calls": 2, "usage": {"prompt_tokens": 1848, "completion_tokens": 870, "cached_tokens": 520}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:21865298", "type": "paper", "label": "pmid:21865298"}, {"id": "source:pmid:21865298", "type": "manuscript", "label": "PMID 21865298 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:21865298", "type": "paper", "label": "pmid:21865298"}, {"id": "source:pmid:21865298", "type": "manuscript", "label": "PMID 21865298 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-21865298", "type": "extraction", "used": ["source:pmid:21865298"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:21865298", "parent_hash": "sha256:4871e50365839dd49fbf13a93e149e1b6b59a221a7e81fc32e7c8a8dd89157bc", "fork_of": null, "generation": 1}, "gaps": ["execution.not_run", "method", "operations", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent"]}