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Case Reports
. 2020 Feb;41(2):412-419.
doi: 10.1002/humu.23939. Epub 2019 Nov 14.

Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia

Carmel G McCullough  1 , Szabolcs Szelinger  2 , Newell Belnap  2 , Keri Ramsey  2 , Isabelle Schrauwen  2 , Ana M Claasen  2 , Leah W Burke  3 , Ashley L Siniard  2 , Matthew J Huentelman  2 , Vinodh Narayanan  2 , David W Craig  1
Affiliations
Case Reports

Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia

Carmel G McCullough et al. Hum Mutat. 2020 Feb.

Abstract

We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.

Keywords: AP-4 deficiency syndrome; AP4S1; intronic variant; spastic paraplegia type 52; splicing.

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