{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:26:20Z","timestamp":1785839180462,"version":"3.56.0"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Congenital anomalies (CAs) with or without intellectual disability (ID)\/developmental delay (DD) comprise a heterogeneous spectrum of diseases that affect approximately 3% of live births worldwide. Recently, whole\u2010exome sequencing (WES) demonstrated the highly heterogeneous genetic causes of CAs. The purpose of this study was to evaluate a referral system to increase the yield of WES for CAs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>From August 2018 to July 2019, patients with CAs, with or without ID\/DD, after excluding gross chromosomal aberrations, were referred to geneticists in two medical centers. Variant prioritization was conducted with an AI\u2010assisted tool for whole exomes or a CA\u2010related gene panel.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Forty patients (27 males and 13 females) with CAs were enrolled in the study with a mean age of 4.71\u2009years (range, 0.01\u201318.2). Pathogenic variants in 14 genes were discovered in 16 patients (three patients with CHD7 and 13 patients with one gene each of ATP6V1B2, TAF6, COL4A3BP, ANKH, BMP2, SMARCA4, CUL4B, PGAP3, SOX11, FBN2, PTPN11, SOS1, or PROKR2), with a positive diagnostic rate of 40%. Among the 16 positive cases, 13 (81%) also had ID\/DD. The inheritance was autosomal dominant in 13 (81%), autosomal recessive in two (13%), and X\u2010linked in one (6%). Only five patients received a correct clinical diagnosis before WES. The analyses of patients with a negative genetic diagnosis revealed a phenotype and gene mutation load similar to those of the positive\u2010finding patients but with a lower percentage of ID\/DD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The careful selection of patients by experienced geneticists and the exclusion of chromosomal aberrations raises the positive rate of the molecular diagnosis for CAs to 40%. However, more than half of the patients with CAs still do not have a genetic diagnosis by current technologies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2160","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T03:34:31Z","timestamp":1677555271000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Utility of whole\u2010exome sequencing for patients with multiple congenital anomalies with or without intellectual disability\/developmental delay in East Asia population"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-9953","authenticated-orcid":false,"given":"Rai\u2010Hseng","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"},{"name":"Department of Pediatrics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-3277","authenticated-orcid":false,"given":"Chen\u2010Hao","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics E\u2010Da Hospital  Kaohsiung Taiwan"},{"name":"School of Medicine I\u2010Shou University  Kaohsiung Taiwan"},{"name":"Department of Pediatrics Kaohsiung Chang Gung Memorial Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-5728","authenticated-orcid":false,"given":"Yin\u2010Hsiu","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"},{"name":"Department of Pediatrics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuan\u2010Pei","family":"Lin","sequence":"additional","affiliation":[{"name":"Rare Disease Center, MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Genetics and Metabolism MacKay Children's Hospital  Taipei Taiwan"},{"name":"Department of Medicine MacKay Medical College  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao\u2010Zi","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai\u2010Chi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Lin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6690-4879","authenticated-orcid":false,"given":"Wuh\u2010Liang","family":"Hwu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"},{"name":"Department of Pediatrics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-7499","authenticated-orcid":false,"given":"Ni\u2010Chung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Taiwan University Hospital  Taipei Taiwan"},{"name":"Department of Pediatrics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1312543"},{"key":"e_1_2_9_3_1","unstructured":"Centers for Disease Control and Prevention.Birth defects. 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