Further Evidence for LRRC7 Gene Involvement in Neurodevelopmental Disorder: A Novel Variant.

BACKGROUND

Neurodevelopmental disorders (NDDs) are clinically heterogeneous conditions with complex etiologies and limited therapeutic options. Here, we investigated a proband presenting global developmental delay (GDD), tonic seizures, failure to thrive, mild microcephaly, intellectual disability (ID), and hypotonia.

METHODS

Exome sequencing (ES), followed by Sanger sequencing, was performed for molecular diagnosis. Gene expression was assessed by reverse-transcriptase quantitative PCR (RT-qPCR), and 3D protein modeling was performed.

RESULTS

ES revealed a novel de novo (heterozygous) missense variant [c.2660C>T; p.(Pro887Leu)], in LRRC7 (NM_001370785.2) gene, located in exon 18, which may contribute to the proband's phenotype. The identified variant was classified as variant of uncertain significant (VUS) according to the American College of Medical Genetics and Genomics Guidelines (ACMG). RT-qPCR showed reduced LRRC7 mRNA expression in the proband compared to control samples, while and 3D protein modeling revealed substantial changes in the LRRC7-secondary structure.

CONCLUSION

Using genetic, molecular, in silico, and expression analysis, we characterize a novel de novo-LRRC7 variant and describe its association with an NDD phenotype.