{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T02:20:38Z","timestamp":1794104438169,"version":"4.8.0"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hypoplastic left heart syndrome (HLHS) is a rare but fatal birth defect in which the left side of the heart is underdeveloped. HLHS accounts for 2% to 4% of congenital heart anomalies. Whole genome sequencing (WGS) was conducted for a family trio consisting of a proband and his parents. A homozygous rare variant was detected in the\n                    <jats:italic>PTPRB<\/jats:italic>\n                    (Protein Tyrosine Phosphatase Receptor Type B) gene of the proband by functional annotation and co\u2010segregation analysis. Sanger sequencing was used to confirm genotypes of the variant. The in silico prediction tools, including Mutation Taster, SpliceAI, and CADD, were used to predict the impact of the mutation. The allele frequencies across populations were compared based on multiple databases, including \u201c1000 genomes\u201d and \u201cgnomAD\u201d. We used two vectors (pcMINI and pcDNA3.1) to generate a minigene construct to validate the mutational effect at the transcriptional level. Family\u2010based WGS analyses showed that only a homozygous splice acceptor variant (NC_000012.12: g.70636068T&gt;G, NM_001109754.4: c.56\u20102A&gt;C, NG_029940.2: g.6373A&gt;C) at the exon\u2010intron border of\n                    <jats:italic>PTPRB<\/jats:italic>\n                    gene associates with HLHS. This variant is also within the region with the enhancer activity based on UCSC genome annotation. Genotyping and Sanger sequencing revealed that the proband's parents are heterozygous for this variant. Evolutionary conservation analysis revealed that the site (NC_000012.12: g.70636068) is extremely conserved across species, supporting the evolutionary functional constraints of the ancestral wild type (T). In silico tools universally predicted a deleterious or disease\u2010causing impact of the mutation from T to G. The mutation was not found in the 1000 genomes and gnomAD databases, which indicates that this mutation is very rare in most human populations. A splicing assay indicated that the mutated minigene caused aberrant splicing of mRNA, in which a 3\u00a0bp missing in the second exon resulted in the deletion of one amino acid (NP_001103224.1:p.Glu19del) compared to the normal protein of\n                    <jats:italic>PRPTB<\/jats:italic>\n                    (also the VE\u2010PTP). Structure prediction revealed that the deletion occurred within the C\u2010region of the signal peptide of VE\u2010PTP, suggesting signal peptide\u2010related defects as a potential mechanism for the HLHS cellular pathogeny. We report a rare homozygous variant with splicing error in\n                    <jats:italic>PTPRB<\/jats:italic>\n                    associated with HLHS. Previous model species studies revealed conserved functions of\n                    <jats:italic>PTPRB<\/jats:italic>\n                    in cardiovascular and heart development in mice and zebrafish. Our study is the first report to show the association between\n                    <jats:italic>PTPRB<\/jats:italic>\n                    and HLHS in humans.\n                  <\/jats:p>","DOI":"10.1111\/cge.14234","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T04:44:33Z","timestamp":1663908273000},"page":"79-86","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel rare mutation in a conserved site of\n                    <scp>\n                      <i>PTPRB<\/i>\n                    <\/scp>\n                    causes human hypoplastic left heart syndrome"],"prefix":"10.1111","volume":"103","author":[{"given":"Yangying","family":"Jia","sequence":"first","affiliation":[{"name":"Institutes for Systems Genetics, Frontiers Science Center for Disease\u2010related Molecular Network, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhai","family":"Chen","sequence":"additional","affiliation":[{"name":"Institutes for Systems Genetics, Frontiers Science Center for Disease\u2010related Molecular Network, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhong","sequence":"additional","affiliation":[{"name":"Institutes for Systems Genetics, Frontiers Science Center for Disease\u2010related Molecular Network, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"He","sequence":"additional","affiliation":[{"name":"Institutes for Systems Genetics, Frontiers Science Center for Disease\u2010related Molecular Network, West China Hospital Sichuan University  Chengdu 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University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdengqieqieke","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Prenatal Diagnosis, Reproductive Medicine Center The First Affiliated Hospital of Xinjiang Medical University  Urumqi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Prenatal Diagnosis, Reproductive Medicine Center The First Affiliated Hospital of Xinjiang Medical University  Urumqi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu 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