# Identification of an additional deep intronic splice variant prompts critical evaluation of SPG7 inheritance

## TL;DR

This study finds that deep intronic variants in SPG7, detectable only by genome sequencing, may explain missing heritability in SPG7-related hereditary spastic paraplegia.

## Contribution

The study reports a novel deep intronic splice variant in SPG7 identified through genome sequencing, challenging assumptions about dominant inheritance.

## Key findings

- A novel deep intronic variant in SPG7 was identified and confirmed to cause a frameshift and premature stop codon.
- Genome sequencing uncovered a second variant in trans, suggesting it may explain missing heritability in SPG7-HSP.
- No strong evidence for true autosomal dominant inheritance in SPG7-HSP was found in literature review.

## Abstract

SPG7-related hereditary spastic paraplegia (SPG7-HSP) is one of the most common forms of autosomal recessive HSP. There is a growing number of reports of affected individuals found to be heterozygous carriers for the recurrent pathogenic coding variants in SPG7, most notably p.Ala510Val, and this has further led to the suggestion of SPG7-HSP having both recessive and dominant forms. Here, we report a proband with pure HSP initially found to carry a heterozygous pathogenic stop-gain variant in SPG7 (NM_ 003119.4:c.1672 A > T; p.Lys558Ter). Subsequent short-read genome sequencing (GS) identified a second, novel deep intronic variant (NM_003119.4:c.987 + 152G > A) in trans, predicted to activate a cryptic splice donor site. RNA sequencing confirmed inclusion of intronic sequence, resulting in a frameshift and premature stop codon (p.Ser330ValfsTer10). This is only the second report of GS uncovering a pathogenic deep intronic variant in SPG7. Our findings highlight that variants only detectable by GS may be an underappreciated disease mechanism and may account for the missing heritability in instances where only a single coding variant is initially identified. Further, critical review of such reports in the literature found no substantial evidence for true autosomal dominant inheritance in SPG7-HSP. These cases most likely represent undetected second variants, alternative molecular diagnoses, or more complex disease mechanisms that have yet to be understood. We recommend the use of GS in individuals with suspected SPG7-HSP carrying only a single pathogenic variant to ensure a complete and accurate molecular diagnosis.