{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T01:25:16Z","timestamp":1773797116997,"version":"3.50.1"},"posted":{"date-parts":[[2025,12,29]]},"group-title":"Genetic and Genomic Medicine","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>TUBB2B<\/jats:italic>\n                  encodes a \u03b2-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in\n                  <jats:italic>TUBB2B<\/jats:italic>\n                  have been associated with a range of neurodevelopmental disorders, with phenotypes including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, likely influenced by variant-specific effects on microtubule formation and stability, an area that warrants further investigation. Homozygous\n                  <jats:italic>TUBB2B<\/jats:italic>\n                  variants are exceedingly rare, with one family reported to date.\n                <\/jats:p>\n                <jats:p>\n                  We describe five individuals in four families with rare\n                  <jats:italic>TUBB2B<\/jats:italic>\n                  variants. Four variant alleles are described, including a previously reported\n                  <jats:italic>de novo<\/jats:italic>\n                  missense variant p.(G98R), with potential phenotypic expansion including panhypopituitarism, a previously reported\n                  <jats:italic>de novo<\/jats:italic>\n                  missense variant, p.(I202T) demonstrating phenotypic heterogeneity between individuals, a\n                  <jats:italic>de novo<\/jats:italic>\n                  missense variant, p.(Q15K) at a polyamination site critical for microtubule stability, and a novel homozygous missense variant located within a region of absence of heterozygosity in two siblings from consanguineous parents p.(V49I). Both individuals also have a pathogenic homozygous truncating variant in\n                  <jats:italic>ALKBH8<\/jats:italic>\n                  p.(R559Afs*56), representing a rare dual molecular diagnosis driving clinical features reflective of contributions from both genes. These cases expand the known clinical spectrum of\n                  <jats:italic>TUBB2B<\/jats:italic>\n                  -related tubulinopathies, illustrate intragenic phenotypic heterogeneity, including with recurrent variants and provide novel insights into potential mechanisms of disease, such as effects at polyamination sites and rare recessive inheritance, underscoring the need for nuanced genotype-phenotype interpretation in both diagnostic and counseling contexts.\n                <\/jats:p>","DOI":"10.64898\/2025.12.28.25342917","type":"posted-content","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T03:50:15Z","timestamp":1767066615000},"source":"Crossref","is-referenced-by-count":1,"title":["Expanding the Clinical and Molecular Spectrum of\n                  <i>TUBB2B<\/i>\n                  Through Distinct Variants Identified Across Multiple Families"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4092-7703","authenticated-orcid":false,"given":"Shaghayegh T.","family":"Beheshti","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angad","family":"Jolly","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed K.","family":"Saad","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haowei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren E.","family":"Westerfield","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chloe","family":"Munderloh","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Divya","family":"Kalra","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Wu","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Claude","family":"Gingras","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shalini N.","family":"Jhangiani","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarenur","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Dr. Sare Nur Yilmaz, Independent Practice, Istanbul, 34758, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha S.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6860-372X","authenticated-orcid":false,"given":"Daniel G.","family":"Calame","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Texas Children\u2019s Hospital, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davut","family":"Pehlivan","sequence":"additional","affiliation":[{"name":"Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Texas Children\u2019s Hospital, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A.","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA"},{"name":"Texas Children\u2019s Hospital, Houston, TX, 77030, 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