Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund–Thomson syndrome

Abstract

Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund–Thomson syndrome (RTS—a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.

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.…”

“…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. 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.…”

Nouvelles formes de dyskératoses congénitales

“…Par consé-quent, les DC causées par des mutations de ces gènes sont invariablement associées à des raccourcissements accélérés des télomères. Dans un sous-groupe de DC de transmission autosomique récessive (dont le phénotype semble peu sévère), des mutations bialléliques du gène C16orf57 ont été mises en évidence [23]. Cependant, aucun signe de dysfonctionnement télomérique n'a été observé chez ces patients dont les télomères sont de taille normale.…”

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).…”