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In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in\n                    <jats:italic>CAPN3<\/jats:italic>\n                    (c.259C\u2009&gt;\u2009G:p.L87V),\n                    <jats:italic>MUSK<\/jats:italic>\n                    (c.1781C\u2009&gt;\u2009T:p.A594V),\n                    <jats:italic>NAV2<\/jats:italic>\n                    (c.1996G\u2009&gt;\u2009A:p.G666R), and\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    (c.595A\u2009&gt;\u2009C:p.N199H).\n                    <jats:italic>CAPN3<\/jats:italic>\n                    ,\n                    <jats:italic>MUSK<\/jats:italic>\n                    , and\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    are established disease genes linked to limb\u2010girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker\u2013Wolff syndrome (WWS; OMIM# 314580), respectively.\n                    <jats:italic>NAV2<\/jats:italic>\n                    is a retinoic\u2010acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease\u2010contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system\u2010muscle connection. We provide evidence from this\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.62565","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T02:10:03Z","timestamp":1637719803000},"page":"735-750","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7359-6832","authenticated-orcid":false,"given":"Isabella","family":"Herman","sequence":"first","affiliation":[{"name":"Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"},{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angad","family":"Jolly","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Medical Scientist Training Program Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moez","family":"Dawood","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Medical Scientist Training Program Baylor College of Medicine  Houston Texas USA"},{"name":"Human Genome Sequencing Center Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada M. 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