X-linked Sideroblastic Anemia via the ALAS2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8111 ALAS2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8111ALAS281479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

X-linked Sideroblastic Anemia (XLSA) is a disorder characterized by a defect in heme synthesis. Patients present with hallmark ringed sideroblasts in erythrocyte precursor cells from bone marrow aspirates due to deposition of iron granules in the mitochondria. Clinical symptoms include non-hemolytic anemia with variable degree of iron overload leading to fatigue, dizziness, rapid heartbeat, and hepatosplenomegaly. In severe cases, chronic iron deposition can result in advanced fibrotic liver disease, cirrhosis, hepatocellular carcinoma, atherosclerosis, arthritis, fatigue, diabetes, hypogonadism, cardiomyopathy, and diffuse skin pigmentation (Camaschella 2008). Age of onset is primarily between ages 25-35, but may present in early childhood (Liu et al. 2013; May and Bishop 1998).

XLSA is caused by mutations in the ALAS2 gene. Mutations in this gene have also been associated with a separate disorder, protoprophyria, which is characterized by acute painful photosensitivity with stinging and burning sensations upon sunlight exposure but without blistering (Bishop et al. 2013). Sideroblastic anemia is also observed in the context of other disease settings including Pearson Syndrome, mitochondrial myopathy with sideroblastic anemia (MLASA), and X-linked sideroblastic anemia ataxia (XLSA/A). Acquired forms of sideroblastic anemia include myelodysplastic syndromes, excess zinc, lead poisoning, and excessive alcohol use (Camashella 2008). Therefore, genetic testing may be helpful in distinguishing between different inherited forms of sideroblastic anemia and ruling out acquired causes of disease.

Genetics

XLSA primarily affects males, accounts for nearly half of inherited cases of congenital sideroblastic anemia and is inherited in an X-linked recessive manner through mutations in the ALAS2 gene (Camaschella 2008; Campagna et al. 2014). About 20% of XLSA cases occur in females due to constitutive skewed X inactivation (Cazzola et al. 2000). XLSA/A, a form of sideroblastic anemia with ataxia, is inherited in an X-linked recessive manner through mutations in the ABCB7 gene (Allikmets et al. 1999). Sideroblastic anemia may also be inherited in an autosomal recessive manner in MLASA via PUS1 mutations or in Thiamin-responsive megaloblastic anemia via SLC19A2 mutations (Camaschella 2008).

Missense mutations occurring through the core functional regions of the protein (exons 5-11) account for the majority of causative variants to date. Nonsense, small deletions/insertions and substitutions in intron 1 affecting the GATA transcription factor binding site have also be reported in rare cases (Campagna et al. 2014; Liu et al. 2013; Ducamp et al. 2013). No gross deletions encompassing full exon(s) have been reported. De novo mutations have been reported in the ALAS2 gene, but are not common for XLSA (Cotter et al. 1999). Causative mutations in the ALAS2 gene are fully penetrant for presence of sideroblasts in bone marrow aspirates; however, the severity of anemia and iron overload varies. The ALAS2 gene encodes an erythroid specific enzyme, delta-aminolevulinic acid synthease 2, which catalyzes the first step of the heme biosynthetic pathway (May and Bishop 1998).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in the ALAS2 gene were found in 16 of 31 patients diagnosed with congenital sideroblastic anemia (Liu et al. 2013). Analytical sensitivity should be high as all mutations reported are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the ALAS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for testing present with non-hemolytic anemia, microcytosis or microcytic anemia with signs of iron overload, and absence of hemoglobin stability or chronic disease. Common laboratory findings include reduced MCV, increased RDW, and variable presence of ring sideroblasts in a bone marrow aspirate (May and Bishop 1998; Liu et al. 2013).

Gene

Official Gene Symbol OMIM ID
ALAS2 301300
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM. 1999. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Human molecular genetics 8: 743–749. PubMed ID: 10196363
  • Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. 2013. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Molecular Medicine 19: 18-25. PubMed ID: 23348515
  • Camaschella C. 2008. Recent advances in the understanding of inherited sideroblastic anaemia. British Journal of Haematology 143: 27–38. PubMed ID: 18637800
  • Campagna DR, Bie CI de, Schmitz-Abe K, Sweeney M, Sendamarai AK, Schmidt PJ, Heeney MM, Yntema HG, Kannengiesser C, Grandchamp B, Niemeyer CM, Knoers NVAM, et al. 2014. X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations: XLSA Due to ALAS2 GATA Binding Site Mutations. American Journal of Hematology 89: 315–319. PubMed ID: 24166784
  • Cazzola M, May A, Bergamaschi G, Cerani P, Rosti V, Bishop DF. 2000. Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females. Blood 96: 4363–4365. PubMed ID: 11110715
  • Cotter PD, May A, Li L, Al-Sabah AI, Fitzsimons EJ, Cazzola M, Bishop DF. 1999. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis. Blood 93: 1757–1769. PubMed ID: 10029606
  • Ducamp S, Schneider-Yin X, Rooij F de, Clayton J, Fratz EJ, Rudd A, Ostapowicz G, Varigos G, Lefebvre T, Deybach J-C, Gouya L, Wilson P, et al. 2013. Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP). Human Molecular Genetics 22: 1280–1288. PubMed ID: 23263862
  • Liu G, Guo S, Kang H, Zhang F, Hu Y, Wang L, Li M, Ru Y, Camaschella C, Han B, Nie G. 2013. Mutation spectrum in Chinese patients affected by congenital sideroblastic anemia and a search for a genotype-phenotype relationship. Haematologica 98: e158–160. PubMed ID: 24323989
  • May A, Bishop DF. 1998. The molecular biology and pyridoxine responsiveness of X-linked sideroblastic anaemia. Haematologica 83: 56–70. PubMed ID: 9542324

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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