{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:45:13Z","timestamp":1791215113174,"version":"4.1.0"},"reference-count":14,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"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":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>For the efficient diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using exome analysis is required. Recently, our group reported the usefulness of a program called EXCAVATOR2, which screens for CNVs from aligned exome data in bam format. This method is expected to contribute to the identification of structural variants and to improve the diagnosis rate, especially for the diagnosis of autosomal recessive disease, when a conventional exome analysis identifies a pathogenic variant in one allele but not the other. Here we report a 2\u2010year\u2010old Japanese boy with an undiagnosed disease. He had severe neonatal asphyxia, severe intellectual disability, intractable seizures, cerebellar and brainstem hypoplasia and dysmorphic features including a prominent supraorbital ridge, thin upper lip, and prominent antihelix. An exome analysis reinforced with a copy number analysis using the EXCAVATOR2 method revealed that the patient had a hemizygous variant in chr2(GRCh37):g.130925108G&gt;A, NM_017951.4 c.832C&gt;T, p.(Arg278*) in <jats:italic>SMPD4<\/jats:italic> that was derived from his father and a deletion of <jats:italic>SMPD4<\/jats:italic> derived from his mother. The presence of the deletion spanning <jats:italic>SMPD4<\/jats:italic> was confirmed by short\u2010read and long\u2010read whole\u2010genome sequencing. The successful diagnosis of this reported patient demonstrates the diagnostic utility of EXCAVATOR2 and overcomes the weakness of exome analysis for the detection of autosomal recessive diseases in nonconsanguineous families, significantly impacting genetic counseling for family planning.<\/jats:p>","DOI":"10.1002\/ajmg.a.62535","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T05:29:54Z","timestamp":1633757394000},"page":"613-617","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A patient with compound heterozygosity of <scp><i>SMPD4<\/i><\/scp>: Another example of utility of exome\u2010based copy number analysis in autosomal recessive disorders"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4039-8899","authenticated-orcid":false,"given":"Mamiko","family":"Yamada","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8122-7180","authenticated-orcid":false,"given":"Hisato","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiki","family":"Shima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Juntendo University Urayasu Hospital  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-7686","authenticated-orcid":false,"given":"Tomoko","family":"Uehara","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine  Tokyo Japan"},{"name":"Department of Pediatrics Central Hospital, Aichi Developmental Disability Center  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6798-8151","authenticated-orcid":false,"given":"Kenjiro","family":"Kosaki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19695"},{"issue":"20","key":"e_1_2_9_3_1","article-title":"Enhanced copy number variants detection from whole\u2010exome sequencing data using excavator2","volume":"44","author":"D'Aurizio R.","year":"2016","journal-title":"Nucleic Acids Research"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphg.65"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0763-0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.08.006"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00762-1"},{"key":"e_1_2_9_10_1","first-page":"1","article-title":"Splitthreader: Exploration and analysis of rearrangements in cancer genomes","author":"Nattestad M. 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