Monozygotic twins with a de novo 0.32 Mb 16q24.3 deletion, including TUBB3 presenting with developmental delay and mild facial dysmorphism but without overt brain malformation

Abstract

Nervous system development is highly dependent on the function of microtubules, which are assembled from tubulin heterodimers containing several α- and β-tubulin isotypes encoded by separate genes. A spectrum of neurological disorders with malformations of the central nervous system has recently been associated with missense mutations in this group of genes. Here, we report two patients, monozygotic twins, carrying a de novo 0.32 Mb deletion of chromosome 16q24.3 including the TUBB3 gene. The patients presented with global developmental delay, mild facial dysmorphism, secondary microcephaly, and mild spastic diplegia. Cerebral magnetic resonance imaging of the patients did not reveal cortical malformations, malformations of the corticospinal tracts, basal ganglia, corpus callosum, or optic nerves. This observation is in contrast to the group of neurological disorders that are associated with heterozygous missense mutations in genes encoding different neuronal α- and β-tubulin isotypes, termed tubulinopathies. On the background of current knowledge regarding the function and genotype-phenotype correlations of mutations in the neuronal tubulin isotypes, the clinical and diagnostic findings in these patients are discussed. To our knowledge, this is the first report of patients with a de novo deletion of the TUBB3 gene. The lack of cortical or other cerebral malformations supports the current hypothesis that TUBB3-related tubulinopathies are caused by altered protein function.

Second trimester fetal MRI features in a fetus with TUBB3 gene mutation

“…A significant portion of tubulinopathies result from de novo mutations [2] . TUBB3 mutation is an exception, wherein most of the reported cases had a familial origin [3 , 4] Fetal ventriculomegaly is seen in approximately 0.9% of all pregnancies, but fetal brainstem kinking is rarely seen on fetal MRI. The combination of fetal ventriculomegaly and brainstem kinking occurs in certain conditions such as alpha-dystroglycanopathies, tubulinopathies, and X-linked hydrocephalus as described by Amir et al.…”

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

“…All 16 affected individuals underwent extensive clinical examination by at least one expert clinical geneticist. Routine genetic testing was performed whenever clinically relevant, including copy-number variation (CNV) analysis by high-resolution array-based comparative genomic hybridization (aCGH) using (1) 180k CytoSure ISCA v2 array (Oxford Gene Technology; individuals 10A-D), (2) 180k SurePrint G3 CGH microarray as described 10 (Agilent; individual 11), or (3) 400k SurePrint G3 CGH microarray, as described 11 (Agilent, individuals 12 and 13). Affected individuals with a negative aCGH result underwent whole-exome sequencing (WES) on an Illumina HiSeq platform according to the following paradigms: (1) trio-based clinical diagnostic WES (individuals 1, 2, 6, 7, and 9), (2) trio-based WES in a research laboratory (individuals 3 and 4), or (3) WES of an affected individual followed by single site testing in parental DNA samples (individuals 5 and 8; see Table S1 for further details).…”

TUBB3 and KIF21A in neurodevelopment and disease

“…TUBB3 deletions: There are no reports that heterozygous or homozygous deletions of TUBB3 result in a human phenotype. There is one report (Grønborg et al, 2015) of monozygotic twins harboring a de novo 0.32 Mb heterozygous deletion of 11 genes over 16q24.3, including TUBB3 and 2 additional OMIM Morbid genes (FANCA and MCIR). The twins had developmental delay, mild lower limb spasticity, secondary microcephaly and slightly delayed myelination on MRI, but none of the callosal, basal ganglia, cerebellar, or brainstem anomalies or ocular phenotypes commonly seen with established TUBB3 pathogenic variants.…”

“…In addition, ClinVar contains five heterozygous contiguous gene deletions containing TUBB3 (National Center for Biotechnology Information. ClinVar; [VCV000058271.2] 3 (accessed May 10, 2023) and, using the same format, VCV000058272.2, VCV000034317.2, VCV000615204.2, VCV000253762.1), all different from Grønborg et al (2015), that are classified as of uncertain significance, benign, or likely benign. There are also three smaller heterozygous deletions within the TUBB3 gene.…”