GNE-Related Disorders, Myopathy and Thrombocytopenia via the GNE Gene

Inclusion Body Myopathy (IBM) is a heterogeneous group of disorders characterized by muscle fibers with rimmed vacuoles and inclusions consisting of filaments with a diameter of 15 to 21 nm (Griggs et al. 1995. PubMed ID: 7486861). The most common disorder of this group is recessively inherited GNE myopathy, caused by pathogenic variants in the GNE gene. This disorder has multiple historical names, including hereditary inclusion body myopathy (HIBM), inclusion body myopathy 2 (IBM2), distal myopathy with rimmed vacuoles (DMRV), Nonaka myopathy, and quadriceps-sparing myopathy (Q-IBM). As the multiple names can be confusing, the disorder was renamed “GNE myopathy” (Huizing et al. 2014. PubMed ID: 24685570), which has since become the commonly used term for this disorder. GNE myopathy generally presents as a slowly progressive distal weakness in young adults in their second or third decades of life. Clinical presentation includes gait disturbance and foot drop secondary to anterior tibialis muscle weakness. Weakness eventually includes the hand and thigh muscles, but commonly spares the quadriceps muscles, even in advanced disease. Affected individuals have progressive wasting of distal, then proximal skeletal muscles in the lower and then upper extremities. This leads to marked disability, including wheelchair use and dependent care, within 10 to 20 years of the initial symptoms (Mori-Yoshimura et al. 2014. PubMed ID: 24656604).

Inherited thrombocytopenias (IT) comprise a heterogeneous group of disorders characterized by platelet counts below the lower limit of normal; 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. The severity of ITs varies and disease may manifest within a few weeks of birth, or in patients with milder forms of IT symptoms may not appear until late adulthood. Given the genotypic and phenotypic heterogeneity found in IT patients, simultaneous genetic testing for a large subset of IT-related genes may provide the most efficient approach for establishing an accurate and timely diagnosis. However, for patients with additional overt clinical features, analysis of a single gene may be an appropriate approach. In particular, sequencing of the GNE gene should be considered in patients with GNE-related myopathy (Mori-Yoshimura et al. 2014. PubMed ID: 25303967).

Variants in GNE are typically associated with recessive GNE myopathy that presents as a slowly progressive distal weakness in young adults in their second or third decades of life (Mori-Yoshimura et al. 2014. PubMed ID: 24656604). However, some patients with GNE myopathy were reported to have autosomal recessive, mild, asymptomatic thrombocytopenia (Mori-Yoshimura et al. 2014. PubMed ID: 25303967). Two recent studies report patients with mild to severe congenital thrombocytopenia with no clinical evidence of GNE myopathy who harbored homozygous or compound heterozygous variants in GNE (Revel-Vilk et al. 2018. PubMed ID: 30171045; Futterer et al. 2018. PubMed ID: 29941673). In addition to large platelets, patients showed bruising and bleeding tendencies including surgery or trauma related bleeding, and in females, severe menorrhagia. One patient in Futterer et al. also had neurological symptoms, developmental delay, and skull abnormalities. Data support increased platelet clearance and turnover compared to healthy controls as a cause of disease since patients had very high levels of immature platelets and platelet aggregation appeared to be unaffected (Revel-Vilk et al. 2018. PubMed ID: 30171045; Futterer et al. 2018. PubMed ID: 29941673). GNE is expressed in all hematopoietic cells and encodes the bi-functional enzyme UDP-N-acetylglucosamine 2-epimerase that is important for sialic acid biosynthesis which is required for normal sialylation in hematopoietic cells. Dysregulated sialic acid biosynthesis has been associated with thrombocytopenia (Li et al. 2017. PubMed ID: 28494777) and may be the mechanism of GNE-related thrombocytopenia. 

Most GNE pathogenic variants are missense variants affecting either the epimerase or kinase enzymatic domains of this bi-functional enzyme; however, nonsense, splice-site, and small frameshift deletions, duplications and insertions are also known (Celeste et al. 2014. PubMed ID: 24796702; Human Gene Mutation Database). GNE Myopathy is the most common genetic disorder among Persian Jews; the carrier rate may be as high as 1:15 (Eisenberg et al. 2001. PubMed ID: 11528398). There are other GNE ethnic founder variants reported in Japanese (Nishino et al. 2002. PubMed ID: 12473753), Indian/Asian (Nalini et al. 2013. PubMed ID: 24005727) and Roma Gypsy (Chamova et al. 2015. PubMed ID: 26231298) populations. To our knowledge, no de novo pathogenic variants have been reported for patients with GNE-related disorders.

Another allelic disorder, Sialuria, is an autosomal dominant inborn error of metabolism caused by mono-allelic GNE missense variants located in the allosteric region of GNE (codons 294-297, based on protein accession NP_001121699). Due to loss of feedback inhibition of GNE epimerase activity, Sialuria subjects experience an uncontrolled overproduction of cytosolic free sialic acid and present with subtle clinical features that include developmental delay, hypotonia, recurrent respiratory infections, and hepatomegaly (Seppala et al. 1999. PubMed ID: 10330343; Leroy et al. 2001. PubMed ID: 11326336; Champaigne et al. 2016. PubMed ID: 27142465).

GNE null pathogenic variants have never been identified on both alleles; this is predicted to be lethal, due to the critical role of sialic acid in early development. This is supported by embryonic lethality of Gne ‘knock-out’ mice (Schwarzkopf et al. 2002. PubMed ID: 11929971). GNE has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Among larger cohorts of patients with suspected GNE Myopathy, bi-allelic pathogenic variants have been detected in all patients (Li et al. 2011. PubMed ID: 21307865; Lu et al. 2011. PubMed ID: 22196754; Cho et al. 2014. PubMed ID: 24027297; Zhao et al. 2015. PubMed ID: 2598633), suggesting a sensitivity approaching 100%. However, detection rates vary based on ethnicity and certainty of clinical diagnosis (O’Ferrall et al. 1993. PubMed ID: 20301439). For example, out of a group of 209 Korean patients with suspected inherited muscular disorders, 7 were found to have bi-allelic GNE variants (~3%) (Park et al. 2017. PubMed ID: 27363342).

The exact sensitivity of detection of larger deletions or duplications involving GNE is unknown. However, in one recent study of 13 patients with clinical features consistent with GNE myopathy and with only a single variant detected by Sanger sequencing, single or multi-exonic deletions or duplications were detected on the second allele of all patients (Zhu et al. 2017. PubMed ID: 27829678). This indicates copy-number testing should be considered for cases in which only a single potentially causative GNE variant is detected via sequencing.

In general, ~50% of inherited thrombocytopenias are not yet characterized (Balduini et al. 2013. 23397552). Variants in GNE are a frequent cause of GNE myopathy and have been reported in only a few, isolated cases of mild to severe thrombocytopenia with no related myopathy.

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the GNE 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.