Genome sequencing reveals novel noncoding variants in PLA2G6 and LMNB1 causing progressive neurologic disease

Abstract

Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients’ clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035‐926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo‐exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis‐acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult‐onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.

Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant

“…As detailed in the Supplements, the index patient was enrolled at the Stanford Center for Undiagnosed Diseases in the frame of the Undiagnosed Diseases Network (UDN) program. Genome sequencing was performed as described (Borja et al, 2022). The structure of CBL complexed with a substrate peptide (PDB 4A49) (Dou et al, 2012) was used to predict the functional relevance of Cys 401 .…”