title: Utility of next-generation sequencing technologies for the efficient genetic resolution of haematological disorders.
abstract: Next-generation sequencing (NGS) has now evolved to be a relatively affordable and efficient means of detecting genetic mutations. Whole genome sequencing (WGS) or whole exome sequencing (WES) offers the opportunity for rapid diagnosis in many paediatric haematological conditions, where phenotypes are variable and either a large number of genes are involved, or the genes are large making sanger sequencing expensive and labour-intensive. NGS offers the potential for gene discovery in patients who do not have mutations in currently known genes. This report shows how WES was used in the diagnosis of six paediatric haematology cases. In four cases (Diamond-Blackfan anaemia, congenital neutropenia (n = 2), and Fanconi anaemia), the diagnosis was suspected based on classical phenotype, and NGS confirmed those suspicions. Mutations in RPS19, ELANE and FANCD2 were found. The final two cases (MYH9 associated macrothrombocytopenia associated with multiple congenital anomalies; atypical juvenile myelomonocytic leukaemia associated with a KRAS mutation) highlight the utility of NGS where the diagnosis is less certain, or where there is an unusual phenotype. We discuss the advantages and limitations of NGS in the setting of these cases, and in haematological conditions more broadly, and discuss where NGS is most efficiently used.
authors.affiliation: T-Life Research Center, Fudan University, Shanghai, 200433, China.|Department of BioMedical Research, BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Haematology Department, The Children's Hospital at Westmead, Sydney, Australia.|Cancer Research Unit, Children's Medical Research Institute, Westmead, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Barbaro
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, Australia.|Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Alodaib
authors.affiliation: Department of BioMedical Research, BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Gold
authors.affiliation: Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, Australia.|Clinical Genetics Department, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Adès
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Human Genetics Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Department of BioMedical Research, BGI-Shenzhen, Shenzhen, 518083, China.|Shenzhen Key Laboratory of Genomics, Shenzhen, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzhen, China.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Haematology Department, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Teo
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Human Genetics Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, Australia.|Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D000293:Adolescent; D001853:Bone Marrow / Q000473:pathology; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D006402:Hematologic Diseases / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male
keywords: Diamond-Blackfan anaemia; Fanconi anaemia; congenital neutropenia; juvenile myelomonocytic leukaemia; macrothrombocytopenia; whole exome sequencing