Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HM) remain unexplored. Here, we analyzed the genomic profiles of 176 HM patients carrying 82 distinct presumably germline DDX41 variants among a group of 9,821 unrelated patients. Using our proposed DDX41 specific variant classification, we identified features distinguishing 116 HM patients with CV from 60 HM patients with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV versus 60% in VUS, P=0.03), frequent concurrent somatic DDX41 variants (79% in CV versus 5% in VUS, p<0.0001), a lower somatic mutation burden (1.4 ± 0.1 in CV versus 2.9 ± 0.04 in VUS, P=0.012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA and FLT3 in AML, and favorable overall survival (OS) in AML/MDS patients. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in AML/MDS patients, regardless of patient's sex, age or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm (MPN) and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.

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The NONO gene encodes a nuclear protein involved in RNA metabolism. Hemizygous loss-offunction NONO variants have been associated with syndromic intellectual disability and with left ventricular noncompaction (LVNC). A two-year-old boy presented to the University of Utah's Penelope Undiagnosed Disease Program with developmental delay, nonfamilial features, relative macrocephaly, and dilated cardiomyopathy with LVNC and Ebstein anomaly. Brain MRI showed a thick corpus callosum, mild Chiari I malformation, and a flattened pituitary. Exome sequencing identified a novel intronic deletion (c.154+5_154+6delGT) in the NONO gene. Splicing studies demonstrated intron 4 read-through and the use of an alternative donor causing the frameshift p.Asn52Serfs*6.Family segregation analysis showed that the variant occurred de novo in the boy's unaffected mother. MRI and endocrine findings suggest that hypopituitarism may contribute to growth failure, abnormal thyroid hormone levels, cryptorchidism, or delayed puberty in patients with NONOassociated disease. Also, including this case LVNC has been observed in five out of eight patients, and this report also confirms an association between loss of NONO and Ebstein anomaly. In some cases, unrelated individuals share the same pathogenic NONO variants but do not all have clinically significant LVNC, suggesting that additional modifiers may contribute to cardiac phenotypes. K E Y W O R D S Ebstein anomaly, left ventricular noncompaction, NONO, splicing variant, syndromic intellectual disability 1 | INTRODUCTION The nonoctamer-containing, POU-domain DNA-binding protein (NONO) is a highly conserved, member of the Drosophila behavior/human splicing (DBHS) protein family thought to be involved in various aspects of RNA metabolism (Shav-Tal and Zipori, 2002). Mice lacking NONO have small cerebellums, spatial memory impairment, and changes at inhibitory synapses (Mircsof et al., 2015). Immunohistochemistry indicates that NONO is broadly expressed in mouse tissues, including in neurons and granule cells of the cortex and hippocampus (Mircsof et al., 2015) as well as in the heart (Scott et al., 2017). Hemizygous loss-of-function variants in the Xq13.1-located NONO gene in patients were initially associated with an intellectual disability syndrome (MIM: 300967), with findings including macrocephaly, nonfamilial features, and thickened corpus callosum (Mircsof et al., 2015). Subsequently, four additional patients were described with these features and with left ventricular noncompaction (LVNC) cardiomyopathy (Reinstein et al., 2016; Scott et al., 2017). To date, five pathogenic NONO alterations have been reported, two of which were observed twice in unrelated patients.Notably, identical NONO variants were variably associated with LVNC. Here we report a patient with shared as well as additional features that confirm and expand the physical, functional, and cardiovascular phenotypes associated with NONO loss. | CLINICAL REPORTThis two-year-old boy at the time of testing was the first-born child of ...

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