A novel family illustrating the mild phenotypic spectrum of TUBB2B variants. (November 2021)

• Record Type: Journal Article
• Authors: Dekker, Jordy; Diderich, Karin E.M.; Schot, Rachel; Husen, Sofie C.; Dremmen, Marjolein H.G.; Go, Attie T.J.I.; Weerts, Marjolein J.A.; van Slegtenhorst, Marjon A.; Mancini, Grazia M.S.
• Is Part Of: European journal of paediatric neurology. Volume 35(2021)
• Page Start: 35
• Page End: 39
• Publication Date: 2021-11
• Subjects: TUBB2B protein -- Tubulin -- Malformations of cortical development -- Microtubules; Pediatric neurology -- Periodicals; Nervous System Diseases -- Periodicals; Child -- Periodicals; Infant -- Periodicals; Neurologie pédiatrique -- Périodiques; Pediatric neurology; Electronic journals; Periodicals; Electronic journals; 618.928
• DOI: 10.1016/j.ejpn.2021.09.007
• Languages: English
• ISSNs: 1090-3798

Abstract

Abstract: TUBB2B codes for one of the isotypes of β-tubulin and dominant negative variants in this gene result in distinctive malformations of cortical development (MCD), including dysgyria, dysmorphic basal ganglia and cerebellar anomalies. We present a novel family with a heterozygous missense variant in TUBB2B and an unusually mild phenotype. First, at 21 3 7 weeks of gestation ultrasonography revealed a fetus with a relatively small head, enlarged lateral ventricles, borderline hypoplastic cerebellum and a thin corpus callosum. The couple opted for pregnancy termination. Exome sequencing on fetal material afterwards identified a heterozygous maternally inherited variant in TUBB2B (NM_178012.4 ( TUBB2B ):c.530A > T, p.(Asp177Val)), not present in GnomAD and predicted as damaging. The healthy mother had only a language delay in childhood . This inherited TUBB2B variant prompted re-evaluation of the older son of the couple, who presented with a mild delay in motor skills and speech. His MRI revealed mildly enlarged lateral ventricles, a thin corpus callosum, mild cortical dysgyria, and dysmorphic vermis and basal ganglia, a pattern typical of tubulinopathies. This son finally showed the same TUBB2B variant, supporting pathogenicity of the TUBB2B variant. These observations illustrate the wide phenotypic heterogeneity of tubulinopathies, including reduced penetrance and mild expressivity, that require careful evaluation in pre- and postnatal counseling. Highlights: TUBB2B variant c.530A > T, p.(Asp177Val) results in a mild tubulinopathy. Pathogenic variants in TUBB2B can result in a variable phenotypic severity. Familial TUBB2B variants are rare and can give intrafamilial variable phenotypes. Fetal imaging is non-specific therefore complicates prenatal counseling.