A number sign (#) is used with this entry because of evidence that thrombocytopenia-12 with or without myopathy (THC12) is caused by homozygous or compound heterozygous mutation in the GNE gene (603824) on chromosome 9p13.

Biallelic mutation in the GNE gene also causes Nonaka myopathy (605820).

Thrombocytopenia-12 with or without myopathy (THC12) is an autosomal recessive disorder characterized by congenital thrombocytopenia apparent from infancy or early childhood. Most affected individuals have bleeding episodes, including petechiae, easy bruising, epistaxis, hematomas, menorrhagia, and increased bleeding after trauma or surgery, although rare patients may have thrombocytopenia without bleeding. Platelets are enlarged (macrothrombocytopenia), and there is an increase of circulating immature platelets, consistent with increased production. Patient platelets show hyposialylation due to GNE mutations, which causes increased removal of platelets from the circulation, shortened platelet lifespan, and resultant thrombocytopenia. In contrast to the thrombocytopenia, which is present since birth or early childhood, features of myopathy usually do not develop until the mid-twenties, similar to Nonaka myopathy (summary by Zhen et al., 2014, Izumi et al., 2014; Bottega et al., 2022).

For a discussion of genetic heterogeneity of thrombocytopenia, see THC1 (313900).

Zhen et al. (2014) reported a Chinese sister and brother who presented in their mid-twenties with distal myopathy associated with biallelic mutations in the GNE gene and asymptomatic thrombocytopenia identified through blood tests. Adverse bleeding events were not reported. They had typical features of distal myopathy, including muscle weakness and atrophy affecting the lower limbs and resulting in difficulty walking and running, increased serum creatine kinase, a myopathic pattern on EMG, and rimmed vacuoles on muscle biopsy. The sister also had marked weakness and atrophy of the hands. Both patients had asymptomatic thrombocytopenia with increased numbers of megakaryocytes on bone marrow aspirate, suggesting compensation.

Izumi et al. (2014) reported 2 Japanese sibs with congenital thrombocytopenia and onset of myopathy with rimmed vacuoles in their late teens. The sister had intermittent nasal bleeding, whereas bleeding episodes were not reported in the brother. Both patients had normal to enlarged platelet size. Bone marrow biopsy in the brother showed increased numbers of megakaryocytes that were morphologically normal. Both patients had elevated levels of platelet-associated IgG (PAIgG). Izumi et al. (2014) suggested that loss of sialic acid on platelets may have exposed senescent cell antigens. The pattern of muscle involvement in both sibs was more proximal, with involvement of the neck, iliopsoas, and paraspinal muscles. They had a waddling gait; the brother became wheelchair-bound at age 24 years. Serum creatine kinase was elevated, and muscle biopsy showed rimmed vacuoles. The brother also had onset of atypical membranoproliferative glomerulonephritis at age 7, which progressed to chronic renal failure; Izumi et al. (2014) noted that GNE mutant mice have been reported to have similar renal pathology (Galeano et al., 2007).

Manchev et al. (2014) reported a brother and sister, 23 and 26 years of age and born of consanguineous parents of West Indian origin, with congenital macrothrombocytopenia. Both sibs had onset of recurrent bleeding episodes in early childhood (2 and 4 years of age). Features included epistaxis and spontaneous hematomas; the sister also had menorrhagia and ovarian cyst ruptures. Laboratory studies showed severe thrombocytopenia with 90% of the platelets being macrocytic. Bone marrow biopsy of the proposita showed abnormal megakaryocytic clusters with no apparent defect in differentiation or ploidization. Neither individual was reported to have features of a myopathy. Whole-exome sequencing identified homozygous missense mutations in 2 different genes: an I74M variant in the PRKACG gene (176893.0001) and a G559R variant in the GNE gene (see MOLECULAR GENETICS), suggesting that both variants contributed to the phenotype in this family.

Revel-Vilk et al. (2018) reported 9 individuals from 3 unrelated families with congenital macrothrombocytopenia and mild to moderate bleeding diathesis without myopathy. Families F1 and F2 were consanguineous and of Palestinian Arab descent. Patients P1-P5 (from F1) ranged from 24 to 42 years of age, patients P6-P8 (from F2) ranged from 6 to 14 years of age, and P9 (family F3) was 11 years of age. Clinical features included easy bruising, epistaxis, menorrhagia, hemorrhagic corpus luteum, and extensive bleeding after surgery or trauma sometimes requiring transfusion. None of the patients, even the older individuals, had features of myopathy or subclinical myopathy. P9 had autism spectrum disorder and hypotonia of the lower extremities, but muscle biopsy was not consistent with GNE myopathy. The patients had increased immature platelets, consistent with increased platelet turnover; bone marrow aspirate from the patients in F2 showed increased numbers of megakaryocytes. Flow cytometric analysis of patient platelets showed decreased levels of sialic acid and low CD42B (606672) compared to controls. Revel-Vilk et al. (2018) noted that the bleeding phenotype in these patients was out of proportion to the degree of thrombocytopenia, suggesting that there also may be a defect in platelet activation. Protein analysis of platelet extracts showed downregulation of platelet activation, adhesion, and wound-healing pathways.

Futterer et al. (2018) reported 2 cousins from a highly consanguineous Pakistani family with severe congenital thrombocytopenia. The 3-year-old proband was born by emergency C-section at 34 weeks' gestation and developed bilateral intraventricular cerebral hemorrhages soon after birth, resulting in neurologic abnormalities, including developmental delay, nystagmus, and hydrocephalus with skull abnormalities. His 7-year-old cousin had recurrent epistaxis and hematomas. Both had macrothrombocytopenia and increased numbers of immature platelets, consistent with rapid platelet clearance. Platelets from the proband showed decreased expression of CD42B. Exome sequencing followed by Sanger sequencing identified homozygous variants of uncertain significance (according to ACMG guidelines) in 3 genes in both patients: G416R in the GNE gene, A509V in the FRMPD1 gene (616919), and glu801del in the ANKRD18A gene (620259). All 3 variants segregated with the disorder in the family, and all mapped to a homozygous region on chromosome 9p13.3. Functional studies of the variants were not performed. Futterer et al. (2018) noted that GNE is widely expressed in hematopoietic progenitors and was likely responsible for the phenotype. Neither patient had signs of myopathy, which may have been related to their young age.

Bottega et al. (2022) reported 2 unrelated boys, 18 months and 4 years of age and both born of consanguineous parents (P1 of Egyptian descent and P2 of Moroccan descent), who presented soon after birth with severe thrombocytopenia. Except for petechiae and minor bruising, neither had clinically significant bleeding. Platelet volume was increased, circulating immature platelets were present, and they had increased numbers of megakaryocytes on bone marrow aspirates. Platelet autoantibodies were not detected. They had normal psychomotor development, no splenomegaly or dysmorphic features, and no evidence of a myopathy.

Huang et al. (2024) reported a 13-year-old boy with a history of continuous epistaxis and purpura since age 5 associated with severe congenital macrothrombocytopenia. Immunosuppressive therapy for presumed immune thrombocytopenia was ineffective. Other than poor overall growth, he had no additional features: no splenomegaly, no muscle weakness, and normal serum creatine kinase. Bone marrow biopsy aspirate showed megakaryocytes of normal numbers and size.

The transmission pattern of THC12 in the family reported by Izumi et al. (2014) was consistent with autosomal recessive inheritance.

In 2 adult Chinese sibs with thrombocytopenia and myopathy, Zhen et al. (2014) identified compound heterozygous mutations in the GNE gene, Y217H and c.1543_1544delGA, resulting in a frameshift and premature termination (Asp515GlnfsTer2). Familial segregation and functional studies of the variants were not performed, but the authors suggested that the mutations would lead to decreased GNE enzymatic activity and reduced production of sialic acid. Loss of sialic acid on the platelet membrane could result in increased hepatic sequestration of platelets and removal of platelets from the circulation.

In 2 adult Japanese sibs with congenital thrombocytopenia and later onset of myopathy, Izumi et al. (2014) identified compound heterozygous missense mutations in the GNE gene (V603L, 603824.0013 and G739S, 603824.0018). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Of note, whole-exome sequencing also identified compound heterozygous missense variants of uncertain significance in the FLNB gene (603381) and a homozygous variant in the CPEB2 gene (610605) (c.627_628insCCG, resulting in S209delinsSP). Both of these latter variants also segregated with THC12 in the family, but were not considered to contribute to that phenotype. Functional studies of the variants and studies of patient cells were not performed. The authors noted that the V603L mutation is the most common GNE mutation in the Japanese population.

In 2 sibs, born of consanguineous parents of West Indian descent, with congenital macrothrombocytopenia, Manchev et al. (2014) identified homozygous missense mutations in 2 different genes: an I74M variant in the PRKACG gene (176893.0001) and a G559R variant in the GNE gene. The mutations, which were found by whole-exome sequencing, both segregated with the disorder in the family. Studies of patient platelets suggested that the PRKACG mutation caused a loss of function, resulting in defective platelet activation, impaired cytoskeleton reorganization, and impaired megakaryocyte proplatelet formation (see BDPLT19, 616176). As GNE was not associated with thrombocytopenia at that time, the GNE variant was not further studied. However, Futterer et al. (2018) suggested that, since GNE has a role in the sialic acid biosynthesis pathway and biallelic mutations had been identified in patients with congenital thrombocytopenia, the GNE variant may have contributed to the phenotype in this family.

In 9 patients from 3 unrelated families with THC12 without myopathy, Revel-Vilk et al. (2018) identified homozygous or compound heterozygous mutations in the GNE gene (see, e.g., L517P, 603824.0019). The patients ranged from 6 to 42 years of age. Functional studies of the variants were not performed.

In 2 unrelated children, each born of consanguineous parents, with THC12 without myopathy, Bottega et al. (2022) identified homozygous mutations in the GNE gene (603824.0020 and 603824.0021). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed reduced GNE protein expression. Patient serum transferrin glycoforms showed higher levels of asialo-, disialo-, and trisialo- forms and decreased tetrasialoforms compared to controls. These findings suggested that the mutations resulted in a partial loss of GNE function.

In a 13-year-old boy, born of unrelated parents, with THC12 without myopathy, Huang et al. (2024) identified compound heterozygous missense mutations in the GNE gene (C594Y, 603824.0022 and P735R, 603824.0023). The mutations, which were found by targeted exome sequencing and confirmed by Sanger sequencing, both occurred in the C-terminal ManNAc kinase domain. Patient platelets showed decreased sialylation compared to controls, suggesting that altered platelet glycans could result in shorter platelet lifespan. Neither mutation was able to restore the loss of cell surface sialylation in Gne-null mouse endothelial cells, indicating that they both result in a loss of function.

Galeano et al. (2007) created knockin mice with the M712T Gne mutation and found that homozygous mutants did not survive beyond postnatal day 3. On postnatal day 2, there was significantly decreased Gne activity in muscle but no myopathic features; rather, the homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy, with segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of podocalyxin (see 602632).

Huang et al. (2024) found that mice homozygous for the GNE P735R mutation developed fatal cerebral hemorrhage at the early embryonic stage. Histologic studies of brains from mutant mice showed defective angiogenesis with fewer and distended vascular sprouts and abnormal megakaryocyte accumulation in the perineural vascular plexus, even though circulating megakaryocytes were decreased. Western blot analysis showed decreased levels of the P735R protein, and there was defective sialic acid biosynthesis and impaired protein sialylation compared to controls. RNA-seq studies of brain tissue from the mutant mice showed abnormal expression of genes related to angiogenesis. These findings suggested a role for Gne in angiogenesis during embryonic development.