{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:36:40Z","timestamp":1747183000243,"version":"3.40.5"},"reference-count":23,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T00:00:00Z","timestamp":1650585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Human Genetics"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic\/splicing mutations are reported for these disorders to date, but \u223c40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T&gt;C) in <jats:italic>CENPJ<\/jats:italic> (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at \u03b8 0.0). RT\u2010PCR of <jats:italic>CENPJ<\/jats:italic> in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript\/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known <jats:italic>CENPJ<\/jats:italic> function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono\/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of <jats:italic>CENPJ<\/jats:italic>\u2010associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO\u2010based therapies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ahg.12469","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T08:24:42Z","timestamp":1650615882000},"page":"245-256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel leaky splice variant in centromere protein J (<i>CENPJ<\/i>)\u2010associated Seckel syndrome"],"prefix":"10.1111","volume":"86","author":[{"given":"Navneesh","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Genetics University of Delhi South Campus  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laxmi","family":"Kirola","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Delhi South Campus  New Delhi India"},{"name":"Department of Molecular and Human Genetics Banaras Hindu University  Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thenral S","family":"Geetha","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Delhi South Campus  New Delhi India"},{"name":"Medgenome Labs  Bangalore India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirti","family":"Mittal","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Delhi South Campus  New Delhi India"},{"name":"Lunenfeld\u2010Tanenbaum Research Institute  Toronto Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayarama","family":"Kadandale","sequence":"additional","affiliation":[{"name":"Center for Human Genetics  Bengaluru Karnataka 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