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We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice\u2010site variants in the <jats:italic>PNKP<\/jats:italic> gene (NM_007254.4): c.1448+1G &gt; A and c.199\u20108_199\u20105del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199\u20108_199\u20105del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the <jats:italic>PNKP<\/jats:italic> locus.<\/jats:p>","DOI":"10.1002\/ajmg.b.33013","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T10:24:45Z","timestamp":1729160685000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of Two Novel <i>PNKP<\/i> Splice\u2010Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations"],"prefix":"10.1002","volume":"198","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8139-6198","authenticated-orcid":false,"given":"Ugo","family":"Sorrentino","sequence":"first","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova 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Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Salviati","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Istituto di Ricerca Pediatrica\u2010IRP Fondazione Citt\u00e0 della Speranza  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Cassina","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova 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