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With the advancement of sequencing technologies, a rapidly increasing number of gene defects has been identified, thereby mirroring the high heterogeneity in immunological and clinical presentations observed in patients. However, for a large majority of patients, no causative single nucleotide variant (SNV) or small indel can be identified using next-generation sequencing. First studies have shown that also copy number variants (CNVs) can cause IEI. Unfortunately, CNVs are not well examined in many routine diagnostic settings and the aim of this study was to assess the number of clinically relevant chromosomal losses and gains in a large cohort. We identified a total of 20 CNVs using whole exome sequencing data of a cohort of 191 patients with a suspected IEI. A definite molecular diagnosis could be made in five patients (2.6%), including pathogenic deletions affecting <jats:italic>ICOS<\/jats:italic>, <jats:italic>TNFAIP3<\/jats:italic>, and 22q11.2. CNVs of uncertain significance were observed in fifteen patients (7.9%), including deletions of 11q22.1q22.3 and 16p11.2 but also duplications affecting entire or parts of genes previously associated with IEI. Importantly, five patients carrying a CNV of uncertain significance also carried pathogenic or likely pathogenic SNVs (<jats:italic>PIK3R1<\/jats:italic>, <jats:italic>NFKB1<\/jats:italic>, <jats:italic>NLRC4<\/jats:italic>, <jats:italic>DOCK2<\/jats:italic>), or SNVs of unknown significance (<jats:italic>NFKB2<\/jats:italic>). This cooccurrence of SNVs and CNVs suggests modifying effects in some patients, and functional follow-up is warranted now in order to better understand phenotypic heterogeneity. In summary, the diagnostic yield of IEI can be increased substantially by evaluating CNVs, which allows an improved therapeutic management in those patients.<\/jats:p>","DOI":"10.1007\/s10875-022-01276-8","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T15:03:58Z","timestamp":1651244638000},"page":"1083-1092","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Copy Number Analysis in a Large Cohort Suggestive of Inborn Errors of Immunity Indicates a Wide Spectrum of Relevant Chromosomal Losses and Gains"],"prefix":"10.1007","volume":"42","author":[{"given":"Rensheng","family":"Wan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5878-0546","authenticated-orcid":false,"given":"Maximilian","family":"Schieck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Caballero-Oteyza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis Virgil","family":"Cochino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Shcherbina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roya","family":"Sherkat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarisse","family":"Wache-Mainier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Sultan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Illig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Grimbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Proietti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Steinemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"issue":"1","key":"1276_CR1","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s10875-020-00758-x","volume":"40","author":"A Bousfiha","year":"2020","unstructured":"Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. 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Approval was granted by the Ethics Committee of the Albert-Ludwigs-University (ethics committee vote no. 295\/13 version 200149, Freiburg, Germany).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Written informed consent was obtained from all individual patients or legal guardians.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"The authors affirm that no consent to publish is required for this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}