{"id":4573,"date":"2025-12-23T09:26:42","date_gmt":"2025-12-23T09:26:42","guid":{"rendered":"http:\/\/sebigec.es\/blog\/?guid=03d7843ff41cc4378e649bb4de40385c"},"modified":"2026-03-20T14:40:24","modified_gmt":"2026-03-20T14:40:24","slug":"refining-the-phenotypic-spectrum-of-pnkp-related-microcephaly-a-study-of-27-new-patients","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2025\/12\/23\/refining-the-phenotypic-spectrum-of-pnkp-related-microcephaly-a-study-of-27-new-patients\/","title":{"rendered":"Refining the phenotypic spectrum of PNKP-related microcephaly: a study of 27 new patients"},"content":{"rendered":"\n<sec><st>Background<\/st>\n<p>Biallelic pathogenic variants in <I>PNKP<\/I> are associated with microcephaly and early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4 and Charcot-Marie-Tooth disease type 2B2.<\/p>\n<\/sec>\n<sec><st>Methods<\/st>\n<p>We describe the clinical and neuroimaging features of 27 new patients with <I>PNKP<\/I> variants. All patients presented with early-onset seizures, congenital microcephaly and intellectual disability. In addition, we compared our results with data in the literature.<\/p>\n<\/sec>\n<sec><st>Results<\/st>\n<p>Twenty-five patients presented with the classic MCSZ phenotype, while two showed a more severe clinical phenotype. The brain imaging features of the 25 patients varied significantly, but widening of the frontal lobe gyri with frontal hypoplasia and prominent cerebellar folia (consistent with atrophy) could point to <I>PNKP-<\/I>related microcephaly . In contrast, the two patients with severe phenotype showed additional brain MRI features of white matter loss and pontocerebellar hypoplasia fulfilling the criteria of microlissencephaly. Exome sequencing identified seven different <I>PNKP<\/I> variants, including two novel ones. The c.1253_1269dup p.(Thr424GlyfsTer49) and c.1381_1383dup p.(Asn461dup) variants, each was recurrent in 10 patients (37%), while the c.1381_1383del p.(Asn461del) variant was recurrent in four patients (14.8%). Haplotype analysis confirmed that the p.Asn461dup variant has a founder effect in our population. No genotype-phenotype correlation was observed in our cohort.<\/p>\n<\/sec>\n<sec><st>Conclusion<\/st>\n<p>Our results provide &lsquo;microlissencephaly&rsquo; as an emerging distinct phenotype linked to <I>PNKP<\/I> variants. As such, <I>PNKP<\/I> variants could be associated with four overlapping subgroups that lie along a unifying phenotypic continuum.<\/p>\n<\/sec>\n","protected":false},"excerpt":{"rendered":"<p>Background<br \/>\nBiallelic pathogenic variants in PNKP are associated with microcephaly and early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4 and Charcot-Marie-Tooth disease type 2B2.<\/p>\n<p>Methods<br \/>\nWe describe the clinical and neuroimaging featu&#8230;<\/p>\n","protected":false},"author":317,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,14],"tags":[83],"class_list":["post-4573","post","type-post","status-publish","format-standard","hentry","category-articulos","category-jmg","tag-jmedgenet"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/4573","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/users\/317"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=4573"}],"version-history":[{"count":3,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/4573\/revisions"}],"predecessor-version":[{"id":13109,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/4573\/revisions\/13109"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=4573"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=4573"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=4573"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}