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The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We have detected 17p13.3 locus one-allele triplication in a\u00a0male proband from family 1 (F1.1), and duplication in a\u00a0male proband from family 2 (F2.1) applying array comparative genomic hybridization (array CGH). The rearrangements mapped to the following chromosomal regions\u2013arr[GRCh38] 17p13.3(960254\u20131291856)\u00d74 in F1.1 and arr[GRCh38] 17p13.3(1227482\u20131302716)\u00d73 in F2.1. The targeted quantitative PCR revealed that the 17p13.3 locus was also duplicated in the second affected member from family 2 (F2.2; brother of F2.1). In the next step, we performed segregation studies using quantitative PCR and revealed that F1.1 inherited the triplication from his healthy father\u2014F1.2, whereas the locus was unremarkable in the mother of F2.1 &amp; F2.2 and the\u00a0healthy son of F2.1. However, the duplication was present in a healthy daughter of F2.2, an asymptomatic carrier. The breakpoint analysis allowed to define the exact size and span of the duplicated region in Family 2, i.e., 78,948\u00a0bp chr17:1225063\u20131304010 (HG38). Interestingly, all symptomatic carriers from both families presented with variable SHFLD3 phenotype. The involvement of secondary modifying locus could not be excluded, however, the Sanger sequencing screening of <jats:italic>BHLHA9<\/jats:italic> entire coding sequence was unremarkable for both families.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We have shed light on the one-allele CNV triplication occurrence that should be considered when a higher probe (over duplication range) signal is noted. Second, all SHFLD3 patients were accurately described regarding infrequent limb phenotypes, which were highly variable even when familial. Of note, all symptomatic individuals were males. SHFLD3 still remains a mysterious ultra-rare disease and our findings do not answer crucial questions regarding the disease low penetrance, variable expression and heterogeneity. However, we have presented some clinical and molecular aspects that may be helpful in daily diagnostic routine, both dysmorphological and molecular assessment, of patients affected with SHFLD3.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-022-02480-w","type":"journal-article","created":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T12:02:55Z","timestamp":1661515375000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SHFLD3 phenotypes caused by 17p13.3 triplication\/ duplication encompassing Fingerin (BHLHA9) invariably"],"prefix":"10.1186","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0509-1696","authenticated-orcid":false,"given":"Ewelina","family":"Bukowska-Olech","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sowi\u0144ska-Seidler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolanta","family":"Wierzba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksander","family":"Jamsheer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"2480_CR1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s13353-013-0178-5","volume":"55","author":"A Sowi\u0144ska-Seidler","year":"2014","unstructured":"Sowi\u0144ska-Seidler A, Socha M, Jamsheer A. 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All individuals were over 18\u00a0years old and agreed to participate in this study via written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"325"}}