Thrombocytopenia 4 via the CYCS Gene

Inherited thrombocytopenias (IT) comprise a heterogeneous group of disorders characterized by platelet counts below the lower limit of normal, below 150,000/µL (150 x 10⁹/L) in adults. Bleeding manifestations of thrombocytopenia range from mild to severe and may include excessive bruising (purpura), petechiae, prolonged bleeding from cuts or from surgical procedures, spontaneous nose bleeds, and in women, heavy menstrual flows. About half of ITs are syndromic disorders characterized by other physical and neurological anomalies, or immunodeficiencies (Balduini et al. 2013. PubMed ID: 23397552). Over 30 genes are known to be associated with ITs. Pathogenic variants in known genes are found in only about 50% of cases (Kunishima and Saito. 2006. PubMed ID: 16169642; Noris and Pecci. 2017. PubMed ID: 29222283). Noris and Pecci divide ITs into three groups: forms characterized by only platelet deficiencies, syndromic ITs with additional congenital defects, and ITs associated with increased risk of developing additional disease such as myelodysplastic syndrome (MDS) and acute leukemia (AL). For additional information regarding inherited hematologic malignancies, see Churpek et al. 2013. PubMed ID: 22691122; Furutani and Shimamura. 2017. PubMed ID: 28297620. It is important to distinguish ITs from immune/idiopathic thrombocytopenias (ITP) in order to inform clinical management and identify potential at risk family members.

CYCS-associated thrombocytopenia is a mild form of autosomal dominant inherited thrombocytopenia. Platelets are typically normal in size and morphology and range in number from 70-80/µL. Patients are not reported to have any obvious bleeding abnormalities or extra hematologic defects (Morison et al. 2008. PubMed ID: 18345000; De Rocco et al. 2014. PubMed ID: 24326104; Uchiyama et al. 2018. PubMed ID: 30051457).

Variants in CYCS show complete penetrance and account for only a small fraction of inherited thrombocytopenias. To date, only a handful of patients having one of only 4 CYCS gene variants, comprised by three missense variants and one small deletion, have been reported (Morison et al. 2008. PubMed ID: 18345000; De Rocco et al. 2014. PubMed ID: 24326104; Uchiyama et al. 2018. PubMed ID: 30051457; Johnson et al. 2016. PubMed ID: 27479822). Missense variants enhance the apoptotic activity of cytochrome c causing dysregulated megakaryopoiesis and ectopic release of platelets within bone marrow rather than into sinusoids which results in thrombocytopenia (Morison et al. 2008. PubMed ID: 18345000; De Rocco et al. 2014. PubMed ID: 24326104). CYCS encodes cytochrome c, a highly conserved protein that is found in the mitochondrial inner membrane and has roles in mitochondrial electron transport, antioxidant defense, and apoptosis.

Over 30 genes are known to be associated with inherited thrombocytopenias. Pathogenic variants in known genes are found in only about 50% of cases (Kunishima and Saito. 2006. PubMed ID: 16169642; Noris and Pecci. 2017. PubMed ID: 29222283). Pathogenic variants in CYCS have been reported in few patients and are likely not a frequent cause of inherited thrombocytopenia (Kunishima et al. 2013. PubMed ID: 23434115).

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV-calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the CYCS gene plus coverage of 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).