Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia

Abstract

Poikiloderma with Neutropenia (PN), Clericuzio‐Type (OMIM #604173) is characterized by poikiloderma, chronic neutropenia, recurrent sinopulmonary infections, bronchiectasis, and nail dystrophy. First described by Clericuzio in 1991 in 14 patients of Navajo descent, it has since also been described in non‐Navajo patients. C16orf57 has recently been identified as a causative gene in PN. The purpose of our study was to describe a spectrum of C16orf57 mutations in a cohort of PN patients including five patients of Athabaskan (Navajo and Apache) ancestry. Eleven patients from eight kindreds were enrolled in an IRB‐approved study at Baylor College of Medicine. Five patients were of Athabaskan ancestry. PCR amplification and sequencing of the entire coding region of the C16orf57 gene was performed on genomic DNA. We identified biallelic C16orf57 mutations in all 11 PN patients in our cohort. The seven new deleterious mutations consisted of deletion (2), nonsense (3), and splice site (2) mutations. The patients of Athabaskan ancestry all had a common deletion mutation (c.496delA) which was not found in the six non‐Athabaskan patients. Mutations in the C16orf57 gene have been identified thus far in all patients studied with a clinical diagnosis of PN. We have identified seven new mutations in C16orf57 in PN patients. One of these is present in all patients of Athabaskan descent, suggesting that c.496delA represents the PN‐causative mutation in this subpopulation. © 2010 Wiley‐Liss, Inc.

Clinical utility gene card for: poikiloderma with neutropenia

“…4,5 Several classes of mutations have been identified, listed here in order of decreasing prevalence: nonsense mutations (c.232C4T, c.243G4A, c.258T4A, c.267T4A, c.415C4T, c.541C4T, c.673C4T); small out-of-frame deletions (c.176_177delG, c.179delC, c.489_492del4, c.496delA, c.531delA, c.683_893 þ 1del12); and splicing alterations, including substitutions at canonical splice junctions or at splice-site consensus sequences (c.265 þ 2T4G, c.266 À1G4A, c.450 À2A4G, c.502A4G, c.504 À2A4C, c.693 þ 1G4T). 2,3,[6][7][8][9][10] No missense mutations have yet been found; c.502A4G can be categorised as a splicing alteration because it leads to the excision of the fourth exon from the mature C16orf57-001 transcript. 2 The most frequent recurrent mutations, c.531delA, c.496delA and c.179delC, reflect three geographical clusters.…”

“…For patients positive for C16orf57 mutations, genetic counselling and surveillance should be provided due to the increased risk of developing MDS/AML before the second decade of life (12 cases); PN is therefore classified as a bone marrow failure syndrome. 2,3,7,10,[12][13][14] To date, solid cancers have only been reported in two PN patients, both of whom developed squamous cell carcinoma of the skin. 10,15 Prevalences of bone marrow failure (including pre-dysplastic anomalies evolving in MDS/AML) and skin cancer in PN are 48% and 5%, respectively.…”

“…10,15 Prevalences of bone marrow failure (including pre-dysplastic anomalies evolving in MDS/AML) and skin cancer in PN are 48% and 5%, respectively. 2,3,7,10,[12][13][14][15][16] 2.6 Negative clinical predictive value (probability of not developing the disease if the test is negative) Assume an increased risk based on family history for a nonaffected person. Allelic and locus heterogeneity may need to be considered.…”

“…10,14 A positive C16orf57 genetic test should alert the doctor in charge about haematological and non-haematological oncological risk. Pre-dysplastic alterations of bone marrow, such as hypocellularity, defects in myeloid-cell maturation and delay of neutrophil maturation, recorded to date in 16 patients 2,7,10,12,14,16 may impact the prognosis. The risk of non-haematological cancer, in particular SSC, which has been reported in two PN patients, 7,10,15,18 should be taken into account in the course of dermatologic follow-up.…”

Incomplete splicing of neutrophil-specific genes affects neutrophil development in a zebrafish model of poikiloderma with neutropenia

“…3 The actual number of reported patients is quite limited, mostly because several PN patients have many similar clinical manifestations with dyskeratosis congenita and Rothmund-Thomson syndrome. 4,5 To date, 40 patients with PN have been reported, [6][7][8][9][10][11][12][13][14][15][16] containing 19 different mutations in the C16orf57 gene that encodes a 265-amino-acid protein, referred to as USB1 (U Six Biogenesis 1). 17,18 In some studies, this protein has also been referred to as MPN1 (Mutated in Poikiloderma with Neutropenia).…”