Variability of bone marrow morphology in <i>G6PC3</i> mutations: Is there a genotype–phenotype correlation or age‐dependent relationship?
Authors: Siddharth Banka, Robert Wynn, William G. Newman
Journal: American Journal of Hematology (2010)

Mutations in G6PC3 cause severe congenital neutropenia Type 4 (SCN4, MIM612541) [1] and the allelic condition, Dursun syndrome (MIM613034) [2]. McDermott et al. recently described two siblings with homozygous G6PC3 mutations and increased expression of CXCR4 with myelokathexis, a contrasting presentation from the previously described patients with SCN4 [3]. We identified four individuals with SCN4, of whom two had bone marrow profiles similar to their description [4]. McDermott et al. raised the possibility of phenotypic variability due to differences in genotype or age. To test this hypothesis, we undertook a genotype–phenotype analysis of the 25 patients with mutations in G6PC3 reported to date and include two previously unreported patients from our center (Table I). Of the 27 patients, 15 are of Middle Eastern ancestry, six are Caucasians, two are Pakistani and in four cases the ethnicity is unreported. Only two patients have compound heterozygous mutations, whereas 25 have homozygous mutations. A total of 16 distinct G6PC3 mutations have now been reported, of which nine are missense, three nonsense, two small deletions, one single-base insertion, and one is a splice-site mutation. Interestingly, five mutations in exon 6 account for 32 mutated alleles in 17 SCN4 patients. This is due to the effect of two more common mutations, p.G260R in Caucasians and p.R253H in patients with Middle Eastern ancestry, suggesting that there are founder mutations in these populations. Bone marrow morphology has been reported in 15 of the 27 patients. Of these, myeloid hypoplasia and/or maturation arrest was reported in eight patients, one with a frameshift mutation (patient 5 in Table I, p.86Efs, age 22 years at the time of description) and seven with missense mutations (patients 6 and 7, p.M116V, both 1 year and patients 12, 15, 16, 18, and 19, p.R253H, aged 26, 3, 4, 6, and 6 years). In contrast, like the patients described by McDermott et al. (patients 22 and 23, p.G260R, aged nine and 13 years), two of our patients (patients 11 and 13, p.R253H, aged 29 and 25 years) also had myeloid hyperplasia. Additionally, the bone marrow of our two new patients (patients 1 and 8, p.P44S and p.M116T, aged 8 and 10 years) and patient number 14 (p.R253H and age 2 years) were of normal cellularity without maturation arrest. From this it is clear that the same mutation can cause either maturation arrest or hypercellular or normocellular bone marrow (e.g., p.R253H). However, it is notable that all four patients reported with myeloid hypercellularity have missense mutations and therefore it is possible that patients with nonsense or frameshift mutations give rise to a different phenotype. There is also no consistent age-dependent relationship for the bone marrow morphology. In summary, our findings do not support a genotype–phenotype or age-dependent relationship for bone marrow phenotype in patients with G6PC3 mutations. We have also reported two new patients with this rare disorder and demonstrated the possibility of founder mutations in patients with Caucasian and Middle Eastern ancestry. At present, the reason for variability of the bone marrow phenotype in patients with mutations in G6PC3 is unknown and further characterisation is warranted. We acknowledge the support of NIHR Manchester Biomedical Research Centre. S.B. performed experiments; R.W. diagnosed the patients and described the bone marrow findings; S.B. and W.G. designed the research, analyzed results, and wrote the paper. Siddharth Banka*, Robert Wynn†, William G. Newman*, * Genetic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, United Kingdom, † Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom.