A Novel Pathogenic TUBA1A Variant in a Croatian Infant Is Linked to a Severe Tubulinopathy with Walker-Warburg-like Features

Abstract

Tubulinopathies are associated with malformations of cortical development but not Walker-Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker-Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker-Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker-Warburg-associated genes confirm this as not a new presentation of Walker-Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of.

Keywords: TUBA1A; generalized myoclonus; hypoplastic genitalia; hypotonia; lissencephaly; macrocephaly; tubulinopathy.

Figure 1

Brain ultrasound and MRI. (a–c). Brain ultrasound demonstrates dilated cerebral hemispheres, thin mantle of brain tissue on the convexity, absent basal ganglia and hypoplastic pons, and cerebellum. (d,e) Brain MRI showing complex anomalies consistent with WWS. (a) Coronary plane. (b) Medio-sagittal plane. (c) Parasagittal plane. (d) Supratentorial. (e) Infratentorial.

Figure 2

Trio pedigree with Sanger sequence chromatogram traces, showing the heterozygous TUBA1A, Chr12 (GRCh38): g.49185518T>C: NM_006009.4: c.848A>G mutation status in the patient (note that reverse sequencing trace is shown; thus, T>C).

Figure 3

A lollipop diagram depicting the mutation landscape for TUBA1A variants reported in clinVar and the H283R mutation. TUBA1A (consists of two main functional domains represented by the green (Tubulin/FtsZ family, GTPase domain-amino acid (aa) 3-213) and red (Tubulin C-terminal domain-aa 263-392). Red upward lollipops represent pathogenic variants, orange downward lollipops represent likely pathogenic variants, a green upward lollipop represents a single likely benign variant, and the blue upward lollipop represents the H283R mutation identified in the patient.

Figure 4

Three-dimensional modelling of TUBA1A Histidine (residue 283) in a neuronal microtubule filament structure. (a) Side view of neuronal human tubulin filament (modelled based on protein structure: 5JCO [13]). Alternating horizontal rows of α-tubulin 1A chain monomers (top row and third row) with dark blue spheres marking the H283 residue that facilitates interaction between adjacent α-tubulin 1A chain monomers. Each tubulin monomer is coloured differently to aid visualisation of interactions. Second and bottom rows are the tubulin-β-3 chain monomers of the microtubule filament. (b) Top view of microtubule filament shown in 4a, highlighting the location of His283 (dark blue spheres) lying deep in the groove between adjacent α-tubulin 1A chain monomers close to the internal surface of the microtubule filament. (c) Blow up of the structure of the His283 residue (dark blue) showing hydrogen bonding with Lys280 (turquoise) in the same α-tubulin 1A chain monomer and Gln85 (green) in the adjacent α-tubulin 1A chain monomer, which is predicted to be disrupted by the pHis283Arg mutation in the patient.