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 $\raisebox{1ex}{$3$}\!\left/ \!\raisebox{-1ex}{$7$}\right.$ 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.

TUBB2B编码 β-微管蛋白的一种同种型和该基因中的显性负变体导致独特的皮质发育畸形 (MCD)，包括脑回异常、畸形基底节和小脑异常。我们提出了一个在TUBB2B中具有杂合错义变体和异常温和表型的新家族。首先，在 21$\raisebox{1ex}{$3$}\!\left/ \!\raisebox{-1ex}{$7$}\right.$孕周超声检查显示胎儿头部相对较小，侧脑室扩大，小脑边缘发育不全，胼胝体较薄。这对夫妇选择终止妊娠。随后对胎儿材料的外显子组测序确定了 TUBB2B 中的杂合母系遗传变体( NM_178012.4 (TUBB2B ) :c.530A > T, p.(Asp177Val))，在 GnomAD 中不存在并被预测为具有破坏性。健康的母亲在童年时期只有语言发育迟缓。这个继承了TUBB2B变体促使重新评估这对夫妇的大儿子，他的运动技能和语言有轻微的延迟。他的 MRI 显示侧脑室轻度扩大，胼胝体变薄，轻度皮质回旋障碍，以及畸形的蚓部和基底神经节，这是肾小管病变的典型模式。这个儿子最终显示出相同的TUBB2B变体，支持 TUBB2B 变体的致病性。这些观察结果说明了肾小管疾病的广泛表型异质性，包括外显率降低和轻度表达，这需要在产前和产后咨询中进行仔细评估。