Genetic screening of children with suspected inherited bleeding disorders

Abstract

Introduction Genetic screening using high‐throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear. Aim To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing. Methods After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes. Results A total of 68 heterozygous class 3‐5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009). Conclusion We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work‐up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.

Strengths and limitations of high‐throughput sequencing for the diagnosis of inherited bleeding and platelet disorders

“…Different HTS studies for diagnostics of BPD have been published but for this review, we have only focussed on the studies that have used the guidelines for variant classification as formulated by the American College of Medical Genetics (ACMG) in 2015 [10]. Figure 2 provides an overview of the diagnostic rates obtained in these studies that however differ in terms of used HTS methods (TS or WES), studied pathologies (platelet disorders, coagulation disorders and bleeding of unknown etiology) and the number of genes and patients included [11][12][13][14][15][16][17][18][19][20][21]. In addition, these studies have used different inclusion criteria ranging from the selection of only patients with a known or suspected etiology (studies with typically high diagnostic rates) to patients with bleeding of unknown etiology and normal laboratory parameters (studies with very low diagnostic rates).…”

“…Other HTS studies have also reported variants in more than one gene but without further specifications if these had a clinical impact for the patient or family [11,[14][15][16][17][18]20]. Such examples of mostly digenic inheritance have recently also been documented in case reports.…”

“…10 Figure 2 provides an overview of the diagnostic rates obtained in these studies that however differ in terms of used HTS methods (TS or WES), studied pathologies (platelet disorders, coagulation disorders, and bleeding of unknown etiology), and the number of genes and patients included. [11][12][13][14][15][16][17][18][19][20][21] Most of these HTS studies provided no detailed information related to the detection of CNV. [11][12][13][14][15][16][17][18][19][20][21] The ThromboGenomics study reported a CNV in 40 of the 2396 tested patients; these were predicted to affect single exons (n = 11), multiple exons (n = 15), or whole genes (n = 14).…”

“…33,34 In the studies using HTS approaches published so far, many variants were categorized as VUS. [11][12][13][14][15][16][17][18][19][20][21] The proportion of reported VUS, as high as 38% in the ThromboGenomics study, underlines the need for international data sharing efforts. 19 It is essential to annotate variants against databases of variants already implicated in rare diseases.…”

“…Most of these HTS studies provided no detailed information related to the detection of CNV 11‐21 . The ThromboGenomics study reported a CNV in 40 of the 2396 tested patients; these were predicted to affect single exons (n = 11), multiple exons (n = 15), or whole genes (n = 14).…”