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Nearly half of all human proteins are acetylated at their N-termini by the NatA N-terminal acetyltransferase complex. NAA10 is evolutionarily conserved as the catalytic subunit of NatA in complex with NAA15, but may also have NatA-independent functions. Several NAA10 variants are associated with genetic disorders. The phenotypic spectrum includes developmental delay, intellectual disability, and cardiac abnormalities. Here, we have identified the previously undescribed NAA10 c.303C>A and c.303C>G p.(N101K) variants in two unrelated girls. These girls have developmental delay, but they both also display hemihypertrophy a feature normally not observed or registered among these cases. Functional studies revealed that NAA10 p.(N101K) is completely impaired in its ability to bind NAA15 and to form an enzymatically active NatA complex. In contrast, the integrity of NAA10 p.(N101K) as a monomeric acetyltransferase is intact. Thus, this NAA10 variant may represent the best example of the impact of NatA mediated N-terminal acetylation, isolated from other potential NAA10-mediated cellular functions and may provide important insights into the phenotypes observed in individuals expressing pathogenic NAA10 variants.

Background: KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia., Case Presentation: A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic., Conclusions: This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.

Current prognostication in myelofibrosis (MF) is based on clinicopathological features and mutations in a limited number of driver genes. The impact of other genetic mutations remains unclear. We evaluated for mutations in a myeloid panel of 54 genes using next-generation sequencing. Multivariate Cox regression analysis was used to determine prognostic factors for overall survival (OS) and leukaemia-free survival (LFS), based on mutations of these genes and relevant clinical and haematological features. One hundred and one patients (primary MF, N = 70; secondary MF, N = 31) with a median follow-up of 49 (1-256) months were studied. For the entire cohort, inferior OS was associated with male gender (P = 0.04), age > 65 years (P = 0.04), haemoglobin < 10 g/dL (P = 0.001), CUX1 mutation (P = 0.003) and TP53 mutation (P = 0.049); and inferior LFS was associated with male gender (P = 0.03), haemoglobin < 10 g/dL (P = 0.04) and SRSF2 mutations (P = 0.008). In primary MF, inferior OS was associated with male gender (P = 0.03), haemoglobin < 10 g/dL (P = 0.002), platelet count < 100 × 10 9 /L (P = 0.02), TET2 mutation (P = 0.01) and CUX1 mutation (P = 0.01); and inferior LFS was associated with haemoglobin < 10 g/dL (P = 0.02), platelet count < 100 × 10 9 /L (P = 0.02), TET2 mutations (P = 0.01) and CUX1 mutations (P = 0.04). These results showed that clinical and haematological features and genetic mutations should be considered in MF prognostication.

We report a 32 year-old Chinese lady with history of tetralogy of Fallot, presented to us with chest pain due to hypocalcemia secondary to hypoparathyroidism. With her dysmorphic facial features and intellectual disability 22q11.2 deletion was suspected and confirmed by genetic study. Clinicians should consider the diagnosis of DiGeorge syndrome in adult patient with past medical history of congenital heart disease, facial dysmorphism, intellectual disability and primary hypoparathyroidism.

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.