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Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD\u2009=\u20092.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the <jats:italic>SEMA3C<\/jats:italic> gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. <jats:italic>SEMA3C<\/jats:italic> encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a <jats:italic>cis<\/jats:italic>-regulatory effect on <jats:italic>SEMA3C<\/jats:italic> expression, making a contribution to dyslexia susceptibility in this family.<\/jats:p>","DOI":"10.1007\/s00439-021-02289-w","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T08:03:06Z","timestamp":1622620986000},"page":"1183-1200","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Whole-genome sequencing identifies functional noncoding variation in SEMA3C that cosegregates with dyslexia in a multigenerational family"],"prefix":"10.1007","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-0642","authenticated-orcid":false,"given":"Amaia","family":"Carrion-Castillo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7474-6735","authenticated-orcid":false,"given":"Sara B.","family":"Estruch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3330-1462","authenticated-orcid":false,"given":"Ben","family":"Maassen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4375-6572","authenticated-orcid":false,"given":"Barbara","family":"Franke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-890X","authenticated-orcid":false,"given":"Clyde","family":"Francks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-1996","authenticated-orcid":false,"given":"Simon E.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"issue":"6","key":"2289_CR1","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1101\/gr.114876.110","volume":"21","author":"A Abyzov","year":"2011","unstructured":"Abyzov A, Urban AE, Snyder M, Gerstein M (2011) CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. 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