Poikiloderma with neutropenia: a novelC16orf57mutation and clinical diagnostic criteria

Abstract

A new syndrome with poikiloderma was described by Clericuzio et al. in 1991.(1) They reported 14 Navajo native Americans, including eight siblings, developing in the first year of life an erythematous rash, which started on the limbs and spread over the trunk and the face. This rash evolved into poikiloderma. All patients had recurrent bacterial infections. First published as Navajo poikiloderma this syndrome is now known as poikiloderma with neutropenia (PN, OMIM 604173). The inheritance is autosomal recessive, and mutations in a new gene, C16orf57, were recently described in two kindreds.(2) Because of the phenotypic overlap between Rothmund-Thomson syndrome (RTS) and PN, a few patients have been reclassified as mutations in the RECQL4 gene for RTS were absent.(2-5) Until now 27 patients have been described with clinical PN.(1-3,5-8) Here, we report the sixth family with PN outside the Navajo population. We found the previously unreported mutation c.243G>A, p.W81X in the C16orf57 gene, thus confirming the relation of this gene to the disease.(2,6) Because the molecular genetic diagnosis is not always available, we propose clinical and laboratory diagnostic criteria for PN.

C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification

“…C16orf57 encodes a protein of unknown molecular function. To date, 19 distinct C16orf57 mutations have been identified in 31 patients with PN (for details, see Supplemental Table S1; Arnold et al 2010;Tanaka et al 2010;Volpi et al 2010;Clericuzio et al 2011;Colombo et al 2012), all of which lead to the generation of truncated, and most likely nonfunctional, proteins. C16orf57 is also mutated in a subset of patients diagnosed with dyskeratosis congenita (DC) and Rothmund-Thomson syndrome (RTS) (Walne et al 2010;Piard et al 2012).…”

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

“…21,22 Since our previous publication, 21 we have identified homozygous USB1 variants in an additional 8 families with features of DC. In 7 of the 8 families, the variant was identified by targeted sequencing and the remaining family (2 cases) underwent WES.…”

Clinical utility gene card for: poikiloderma with neutropenia

“…A list of major and minor criteria has been proposed for PN patients, 6 but their specificity, sensitivity, and positive and negative predictive values have not been determined and validated.…”

“…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.…”