Phenotype-Genotype Correlation in a Case of Infantile Hypotonia and Epilepsy: A Study of the Clinical Significance of Two Variants of Uncertain Significance in HIVEP2 and LINGO1

Abstract

Genetic causes of neurodevelopmental disorders are frequent and complex. We Report The case of a 10-month-old infant followed for psychomotor delay, severe hypotonia, spastic movements of the lower limbs, and focal seizure with impaired consciousness. Whole-exome sequencing revealed rare variants in the HIVEP2 (NM_006734.3: c.6528_6539del; p. (Gly2177_Gln2180del)) and LINGO1 (NM_032808.5: c.829G>A; P. (Ala277Thr)) genes, classified as two variants of uncertain significance (VUS). Our observation finds a correlation between the patient's clinical presentation and genetic findings and proposes to expand the phenotypic spectrum associated with mutations in HIVEP2 and LINGO1 genes. It also illustrates their possible convergence in the genesis of severe neurodevelopmental disorders. We discuss the potential synergistic effect of mutations in distinct genes involved in neurodevelopmental pathways, and a reflection on the challenges related to VUS interpretation, especially when multiple genes are associated.