Severe Prenatal Presentation of Adenylosuccinate Lyase Deficiency Caused by a Synonymous ADSL Variant Inducing Aberrant Splicing

TL;DR

This study reports a rare prenatal case of a metabolic disorder caused by a previously unreported genetic variant that disrupts protein production.

Contribution

The first confirmed case of prenatal-onset ADSL deficiency caused by a pathogenic synonymous variant inducing aberrant splicing is identified.

Findings

A severe prenatal-onset case of ADSL deficiency was functionally confirmed.

A synonymous ADSL variant was found to cause aberrant splicing, a novel pathogenic mechanism.

Reduced ADSL activity was observed in PBMCs of unaffected parents for the first time.

Abstract

What is already known about this topic?◦ADSL deficiency is a rare metabolic disorder, typically diagnosed postnatally with variable severity.◦ADSL activity is known to be reduced in affected patients.◦Pathogenic variants in ADSL are predominantly missense or truncating; no pathogenic synonymous variants have been reported.What does this study add?◦The first functionally confirmed case of severe prenatal‐onset ADSL deficiency is described.◦The first pathogenic synonymous ADSL variant causing aberrant splicing is identified.◦Reduced ADSL activity in PBMCs of unaffected parents is demonstrated for the first time.

What is already known about this topic?

ADSL deficiency is a rare metabolic disorder, typically diagnosed postnatally with variable severity.

ADSL activity is known to be reduced in affected patients.

Pathogenic variants in ADSL are predominantly missense or truncating; no pathogenic synonymous variants have been reported.

What does this study add?

The first functionally confirmed case of severe prenatal‐onset ADSL deficiency is described.

The first pathogenic synonymous ADSL variant causing aberrant splicing is identified.

Reduced ADSL activity in PBMCs of unaffected parents is demonstrated for the first time.

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