title: Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene.
abstract: Next-generation sequencing is a straightforward tool for the identification of disease genes in extended genomic regions. Autozygosity mapping was performed on a five-generation inbred Italian family with three siblings affected with Clericuzio-type poikiloderma with neutropenia (PN [MIM %604173]), a rare autosomal-recessive genodermatosis characterised by poikiloderma, pachyonychia, and chronic neutropenia. The siblings were initially diagnosed as affected with Rothmund-Thomson syndrome (RTS [MIM #268400]), with which PN shows phenotypic overlap. Linkage analysis on all living subjects of the family identified a large 16q region inherited identically by descent (IBD) in all affected family members. Deep sequencing of this 3.4 Mb region previously enriched with array capture revealed a homozygous c.504-2 A>C mismatch in all affected siblings. The mutation destroys the invariant AG acceptor site of intron 4 of the evolutionarily conserved C16orf57 gene. Two distinct deleterious mutations (c.502A>G and c.666_676+1del12) identified in an unrelated PN patient confirmed that the C16orf57 gene is responsible for PN. The function of the predicted C16orf57 gene is unknown, but its product has been shown to be interconnected to RECQL4 protein via SMAD4 proteins. The unravelled clinical and genetic identity of PN allows patients to undergo genetic testing and follow-up.
authors.affiliation: Università degli Studi di Milano, Dipartimento di Biologia e Genetica per le Scienze Mediche, Milan, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Volpi
authors.forename: Gaia
authors.initials: G
authors.lastname: Roversi
authors.forename: Elisa Adele
authors.initials: EA
authors.lastname: Colombo
authors.forename: Nico
authors.initials: N
authors.lastname: Leijsten
authors.forename: Daniela
authors.initials: D
authors.lastname: Concolino
authors.forename: Andrea
authors.initials: A
authors.lastname: Calabria
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.forename: Michele
authors.initials: M
authors.lastname: Fimiani
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Eric F P M
authors.initials: EF
authors.lastname: Schoenmakers
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D019143:Evolution, Molecular; D005260:Female; D023281:Genomics; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009503:Neutropenia / Q000235:genetics*; D016366:Open Reading Frames; D010375:Pedigree; D011038:Rothmund-Thomson Syndrome / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D012871:Skin Diseases / Q000235:genetics*