Novel Homozygous LAMC3 Frameshift Variant Associated with Confluent Leukoencephalopathy and Low-Grade Tectal Glioneuronal Tumor: Expanding the Phenotypic Spectrum with Bioinformatic Characterization
TL;DR
The LAMC3 phenotype is expanded to include leukoencephalopathy and a co-occurring low-grade tectal glioneuronal tumor is reported as a novel, single-case observation, supporting inclusion of LAMC3 in the differential diagnosis of pediatric leukoencephalopathies, particularly with consanguinity.
Abstract
Background: Biallelic loss-of-function variants in LAMC3, encoding laminin gamma-3, cause occipital cortical malformation (OMIM#614115). White matter disease and intracranial neoplasia have not been reported in this spectrum. We report a novel homozygous LAMC3 frameshift variant, expanding its phenotypic and molecular spectrum. Methods: Two adolescent siblings from a consanguineous Turkish family underwent whole-exome sequencing, with segregation confirmed by NGS/IGV and classification per ACMG/AMP criteria. In silico analyses included multiple sequence alignment, AlphaFold modeling of wild-type and mutant proteins, and docking against nidogen-1 (NID1). Results: Both siblings had a novel homozygous LAMC3 variant frameshift variant (NM_006059.4: c.1852_1882del; p.(Pro618Serfs*5)), classified as pathogenic (PVS1, PM2, PP3, PP1) with full cosegregation. Proband II.III, a 17-year-old female, developed postoperative epilepsy after resection of a tectal low-grade glioneuronal tumor harboring a somatic KRAS (NM_004985.3) p.(Gln61Lys) variant (VAF 42.9%), with periventricular white matter gliosis. Proband II.IV, a 15-year-old male, presented with confluent leukoencephalopathy, occipital pachygyria, parietal polymicrogyria, and subcortical band heterotopia, illustrating striking intrafamilial discordance. Conclusions: Docking analysis revealed that the cleavage removes the C-terminal nidogen-binding region, eliminates the predicted wild-type interface (residues 906–1029), and shifts the binding to an unnatural N-terminal surface. This finding is a hypothesis-generating result consistent with loss of function. This study expands the LAMC3 phenotype to include leukoencephalopathy and reports a co-occurring low-grade tectal glioneuronal tumor as a novel, single-case observation, supporting inclusion of LAMC3 in the differential diagnosis of pediatric leukoencephalopathies, particularly with consanguinity.