Aplastic Anemia and Myelodysplastic Syndrome via the SRP72 Gene

Aplastic Anemia (AA) is characterized by insufficient hematopoiesis and failure of bone marrow cells to produce enough mature blood cells (red blood cells, white blood cells, and megakaryocytes/platelets). Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and hypercellular bone marrow. AA and MDS may represent a continuum whereby AA progresses to MDS. In addition, MDS progression to acute myeloid leukemia (AML) has also been reported in up to 40% of patients (Heaney et al. 1999). AA onset can occur at any age, and in most cases the cause is unknown. Less frequently, AA is linked to a hereditary bone marrow failure disorder such as Fanconi anemia, Shwachman-Diamond syndrome, Dyskeratosis Congenita, or Diamond-Blackfan Anemia. In hereditary cases, AA is usually diagnosed in childhood. MDS and AML are most often sporadic, late-onset malignancies. However, recent data indicate that hereditary MDS/AML may have a higher incidence than was thought previously, and may also have a younger age of onset than sporadic cases (Bannon et al. 2016; Churpek and Godley 2016; www.aamds.org for more information). In a recent publication detailing diagnosis and management of inherited myeloid malignancies, Churpek and Godley point out that germline testing was positive in 11-24% of patients who presented reasonable suspicion of an inherited hematopoietic malignancy (Churpek and Godley 2016; see also Zhang et al. 2015; Churpek et al. 2015; Knight Johnson et al. 2015) and note that these detection rates justify germline genetic testing.

Variants in the SRP72 gene are associated with AA, MDS, pancytopenia, and congenital nerve deafness (Kirwan et al. 2012). To date, few families have been identified with pathogenic SRP72 gene variants and AA/MDS, and reported variants include one small deletion resulting in premature protein termination and one missense variant (Kirwan et al. 2012). Inheritance appears to be autosomal dominant with complete penetrance for either AA or MDS. Functional studies have shown that SRP72 protein harboring one of the familial variants described in Kirwan et al. 2012 is mis-localized within cells. SRP72 encodes a component of the signal recognition particle (SRP) responsible for transport of membrane bound and excreted proteins to the endoplasmic reticulum, but exactly how a defect in protein translocation might result in AA/MDS remains unclear (Kirwan et al. 2012).

Variants in the SRP72 gene have been reported in only two cases of familial aplastic anemia (AA)/ myelodysplastic syndrome (MDS) (Kirwan et al. 2012). Consequently, although the sensitivity of SRP72 sequencing for AA/MDS patients is not precisely known, it is expected to be low.

To the best of our knowledge, large deletions or duplications have not been reported in the SRP72 gene; one missense variant and a small deletion of two nucleotides resulting in premature protein truncation are the only reported SRP72 variants in AA/MDS patients to date.

This test provides full coverage of all coding exons of the SRP72 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.