# X‐Linked Sideroblastic Anaemia Caused by Intronic ALAS2 Variant Resulting in Highly Variable Expressive Phenotype in Male Siblings, a Case Report

## TL;DR

Two brothers with X-linked sideroblastic anemia show very different symptoms due to an intronic mutation in the ALAS2 gene.

## Contribution

Highlights variable expressivity of XLSA and challenges in diagnosing intronic ALAS2 mutations.

## Key findings

- One brother required transfusions and a bone marrow transplant, while the other had mild symptoms.
- An intronic ALAS2 variant was identified and reclassified as pathogenic after initial screening missed it.

## Abstract

X‐linked sideroblastic anaemia (XLSA) is a rare hereditary disorder caused by mutations in the ALAS2 gene, essential for haem biosynthesis. We report two male siblings, the first of whom developed severe microcytic hypochromic anaemia requiring regular transfusions, iron chelation and an allogeneic bone marrow transplant, while his brother displayed only mild microcytic hypochromic indices without anaemia. Initial genetic screening did not identify a pathogenic variant. However, duo exome sequencing later revealed an intronic ALAS2 mutation, initially categorised as of uncertain significance and subsequently reclassified as pathogenic. This case underscores the diagnostic challenges posed by intronic mutations and the highly variable expressivity of XLSA, even among siblings.

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