Multigene testing for inherited thrombocytopenia can detect an unexpected diagnosis as demonstrated in the case report from Ming-Ping et al., where the mode of inheritance and clinical phenotype did not point towards dominant Schlafen family member 14 (SLFN14) moderate thrombocytopenia. They describe two siblings with very severe thrombocytopenia due a pathogenic SLFN14 variant and gonosomal mosaicism in their healthy mother. In their paper Ming-Ping et al. describe two siblings with severe thrombocytopenia (platelets counts <15 × 109/l) and bleeding symptoms, born from healthy non-consanguineous parents.1 The first child died at the age of 5 months due to intracranial haemorrhage. This child also had larger platelets, while this was not found for his affected sister. She has received regular platelet transfusions since birth. Neonatal and immune thrombocytopenia were ruled out. Their diagnosis was made after using whole-exome sequencing with the detection of a heterozygous pathogenic SLFN14 variant that is responsible for dominant thrombocytopenia. Interestingly, gonosomal mosaicism for this variant was detected in the mother who has normal platelet counts. This case report nicely demonstrates the power of multigene sequencing for the diagnosis of inherited thrombocytopenia, which is an extremely heterogenous disorder with already 40 diagnostic-grade genes as potential underlying cause (Figure 1).2, 3 Using only textbook knowledge, the diagnosis of SLFN14-related thrombocytopenia could probably never have been made for these patients. Based on the clinical phenotypes present in the family members, a recessive form of inherited (macro)thrombocytopenia was expected as parents have a normal platelet count. In addition, SLFN14-related thrombocytopenia is an ultrarare disorder and clinical and laboratory data have only been described for four unrelated pedigrees.4 All patients with pathogenic SLFN14 variants have platelet counts >65 × 109/l (moderate thrombocytopenia) and highly variable degrees of bleeding symptoms and International Society of Thrombosis and Haemostasis (ISTH) bleeding scores ranging between 2 and 20. The children in this case report have a much more severe phenotype and still they carry the same genetic variant as previously described.4 In the past, several diagnostic algorithms have been proposed to assist clinicians in the differential diagnosis of inherited thrombocytopenia. The classification of inherited thrombocytopenia was typically driven by the presence or absence of other clinical features besides a platelet defect (syndromic versus non-syndromic), the mode of inheritance (recessive, dominant and X-linked) and the platelet size (macro, micro and normal size platelets) (Figure 1).5 Applying such an algorithm was very useful, as the numbers of genes implicated in inherited thrombocytopenia was less than half of the genes we know today. However, this algorithm would have missed the diagnosis in the family. Since the discovery of many novel genes for inherited thrombocytopenia using next-generation sequencing approaches over the last decade, phenotype–genotype associations for this disorder have become very complex.6 In addition, the mode of inheritance has expanded for well-known genes (e.g., dominant mild Bernard–Soulier syndrome versus the classical recessive form and recessive Fli-1 proto-oncogene, ETS transcription factor [FLI1] and growth factor-independent 1B transcriptional repressor [GFI1B] variants versus the known dominant forms of this type of thrombocytopenia). To date, multigene panel testing is typically used to diagnose inherited thrombocytopenia by investigating all the known genes involved in this pathology in a single analysis.7 Providing detailed clinical and laboratory information to genetic laboratories remains very important for the interpretation of this test as it assists in the variant classification to decide if a variant is pathogenic or not. The major drawbacks of performing a multigene panel test for inherited thrombocytopenia are the detection of many variants of unknown significance than cannot be used for clinical management and unsolicited findings. If for example pathogenic variants are detected in either RUNX family transcription factor 1 (RUNX1), ETS variant transcription factor 6 (ETV6) or ankyrin repeat domain-containing 26 (ANKRD26) in a patient with thrombocytopenia without a family history of leukaemia, such variants can be considered as an unsolicited finding if the patient was not aware about these genetic risk factors for leukaemia before initiating the multigene test. On the other hand, a multigene test allows the detection of ‘the unexpected diagnosis’. This case report provides such an example as a SLFN14 defect was not really expected based on the known disease phenotypes associated with pathogenic variants in this gene.