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Male patients usually have missense variants, but the effects of base substitutions on mRNA splicing have not been investigated. Here, we report a Japanese brother with intellectual disability, characteristic facial appearance with blepharophimosis, cleft palate, Fallot tetralogy, vesicoureteral reflux, and deafness. A known missense pathogenic variant was detected in <jats:italic>MED12<\/jats:italic>, NM_005120.3:c.887G&gt;A p.(Arg296Gln), and X\u2010linked Ohdo syndrome was diagnosed in combination with their phenotype. mRNA splicing of <jats:italic>MED12<\/jats:italic> was evaluated qualitatively and quantitatively using long\u2010range PCR\u2010based targeted RNA sequencing (reverse transcribed long amplicon sequencing), and it was shown that this missense variant simultaneously causes aberrant splicing of the 42\u2010bp in\u2010frame deletion in exon 7, r.847_888del, which accounts for approximately 30% of the mRNAs in both siblings. The X chromosome inactivation study showed that the X chromosome carrying the mutant allele was 100% inactivated in the carrier mothers. mRNA level analysis is essential for the accurate interpretation of the effects of variants. In this case, the MED12 protein function may be reduced by more than just an amino acid substitution, resulting in the patients with the most severe phenotype of MED12\u2010related syndrome in males.<\/jats:p>","DOI":"10.1002\/ajmg.a.63628","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T08:49:15Z","timestamp":1713948555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Qualitative and quantitative analysis of <i>MED12<\/i> c.887G&gt;A causing both missense and splicing variants in X\u2010linked Ohdo syndrome"],"prefix":"10.1002","volume":"194","author":[{"given":"Sumihito","family":"Togi","sequence":"first","affiliation":[{"name":"Center for Clinical Genomics Kanazawa Medical University Hospital  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Ura","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics Kanazawa Medical University Hospital  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-7962","authenticated-orcid":false,"given":"Yo","family":"Niida","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics Kanazawa Medical University Hospital  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"issue":"6","key":"e_1_2_10_2_1","first-page":"1229","article-title":"Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen\u2010receptor gene correlates with X chromosome inactivation","volume":"51","author":"Allen R. 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