# Case report: A novel 11-bp deletion in exon 11 causing a frameshift in the C-terminal of the ALAS2 gene leading to X-linked sideroblastic anemia—a family study

## TL;DR

A new mutation in the ALAS2 gene causes X-linked sideroblastic anemia, affecting a family with anemia and iron overload that improved with treatment.

## Contribution

A novel 11-bp deletion in the ALAS2 gene is identified as a cause of X-linked sideroblastic anemia.

## Key findings

- The 11-bp deletion in exon 11 of ALAS2 leads to a frameshift and a non-functional 614 amino acid protein.
- The mutation disrupts cofactor interaction and responds to pyridoxine and iron chelation therapy.
- Family screening showed male siblings were affected, while female carriers were asymptomatic.

## Abstract

X-linked sideroblastic anemia (XLSA) (MIM 300752) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. It is due to mutations of the erythroid-specific enzyme ALAS2, the first enzyme of the heme biosynthetic pathway. Herein, we report a novel 11-bp deletion in exon 11 leading to a frameshift in the C-terminal region of the ALAS2 gene with a non-functional longer polypeptide of 614 amino acids leading to a loss-of-function mutation manifested as an X-linked sideroblastic anemia phenotype. The proband was a 29-year-old man with moderately severe microcytic hypochromic anemia with splenomegaly and increased ring sideroblasts in the bone marrow with considerable iron overload. Sanger sequencing documented a missense mutation leading to a frameshift with an elongated polypeptide of 614 AA instead of the normal 587 AA protein c.1743_1753 del (p.Gln581Hisfs*35). This mutation affected the interaction with cofactor pyridoxal 5′-phosphate since the patient’s hemoglobin improved with oral administration of pyridoxine tablets. His iron overload also responded to sustained oral iron chelation therapy with deferasirox. The screening of the entire family’s kindred revealed that two other male siblings were also hemizygous for the same mutation with hypochromic microcytic anemia and tissue iron overload, whereas, three female siblings and their mother were heterozygous for the mutant allele. They did not have anemia or iron overload.