Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

Abstract

Background: Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH.

Case presentation: We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus.

Conclusion: We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.

Keywords: Case report; LAMC3; Lobe; Occipital; Periventricular nodular heterotopia.

Fig. 1

Neurological phenotype of a family with biallelic missense variants in LAMC3. a Pedigree of the non-consanguineous family. b Morphology ultrasound at 19 + 4 weeks gestation showing unilateral ventricular dilatation and irregularity of the cerebral ventricular wall (indicated by arrows). c Fetal MRI at 20 + 0 weeks gestation showing multiple foci of periventricular nodular heterotopia in the occipital lobes (indicated by arrows) [Axial T2 weighted image, 4 mm thick slices]. d Post mortem MRI at 21 + 5 weeks gestation shows extensive bilateral posterior periventricular heterotopia (indicated by arrows) [Coronal T2 weighted image, 2 mm thick slices]. e Coronal sections of the cerebrum (frontal top left to occipital bottom right). Macroscopically the brain shows normal gyration for gestation, with no evidence of polymicrogyria or loss of sulci usually visible at 21 weeks gestation to suggest early pachygyria. Subependymal nodularity is present within the occipital horns of the lateral ventricles (indicated by arrows). No further structural malformations of the brain are evident. f Microscopic image of a subependymal periventricular nodular heterotopia within the occipital horn of the lateral ventricle. The well circumscribed nodule is composed of disorganised primitive neurons within glioneuronal tissue. (Scale = 500 µm)