Gene

Whole genome sequencing

Biology

Hereditary spastic paraplegia

Ataxia

Mutation

Psychiatry

DNA sequencing

Computational biology

Genetics

Exome sequencing

Bioinformatics

Genome

Sanger sequencing

Exome

Medicine

splice

Phenotype

Annals of Clinical and Translational Neurology

Objective To identify causative mutations in a patient affected by ataxia and spastic paraplegia. Methods Whole‐exome sequencing (WES) and whole‐genome sequencing (WGS) were performed using patient's DNA sample. RT‐PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot. Results A novel missense variant in SPG7 (c.2195T&gt; C; p.Leu732Pro) was first found by whole‐exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A&gt;G) was identified by whole‐genome sequencing (WGS). RT‐PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts. Interpretation Identification of a deep intronic variant in SPG7 , which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7 , and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.

A deep intronic splice variant advises reexamination of presumably dominant <i>SPG7</i> Cases

A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases