Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype

Springer Science and Business Media LLC - Tập 13 - Trang 1-9 - 2012
Bridget A Fernandez1,2,3, Jane S Green1, Ford Bursey2,3, Brendan Barrett2,3, Andrée MacMillan3, Sarah McColl3, Sara Fernandez3, Proton Rahman2,3, Krista Mahoney1, Sergio L Pereira4, Stephen W Scherer4, Kym M Boycott5, Michael O Woods1
1Discipline of Genetics, Memorial University of Newfoundland, Health Sciences Centre, Newfoundland and Labrador, Canada
2Discipline of Medicine, Memorial University of Newfoundland, St John’s, Newfoundland and Labrador, Canada
3Eastern Health, St John’s, Canada
4The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
5Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada

Tóm tắt

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

Tài liệu tham khảo

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