Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects.

Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11×109/L to 186×109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified "pathogenic" or "likely pathogenic" variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.

Recent advances in diagnosis and treatment of atypical haemolytic uraemic syndrome.

New understanding of the underlying pathology of the thrombotic microangiopathies has resulted in guidelines for the investigation and management of atypical haemolytic uraemic syndrome in children and adults and the prospect of new therapies, which are in clinical trial. Patients should be investigated for defects in complement pathways and a trial of plasma exchange is indicated.

Update on the management of immune thrombocytopenic purpura in children.

PURPOSE OF REVIEW: Since the publication of management guidelines from the American Society of Hematology (1996) and the British Committee for Standards in Haematology (2003), issues surrounding the diagnosis and treatment of immune thrombocytopenic purpura in children continue to evolve. Reports of the last decade are reviewed here. RECENT FINDINGS: Few data support a change in the diagnostic approach to childhood immune thrombocytopenic purpura. Recent publications have again challenged the need to treat minimally symptomatic children with severely low platelet counts and confirmed that anti-D immune globulin is a front-line treatment option. The management of chronic disease in children is essentially the same as in acute cases that become persistent or refractory to treatment. During the past 3 years, noncontrolled studies have suggested that rituximab may be useful for persistent disease. Elsewhere, encouraging evidence suggests that the effect of splenectomy for children is durable in the long term. SUMMARY: The decision to treat or only observe the minimally symptomatic child with severe thrombocytopenia remains controversial. This ongoing debate has served as a mandate to develop and implement clinical scoring and quality of life tools in treatment and clinical trial design. Meanwhile, experiences with adult cases have introduced new drug treatment options for children, especially those with chronic disease and significant bleeding.