The KMT2A (formerly MLL) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. KMT2A is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 KMT2A fusion partners have been identified until now, including the most recurring ones—AFF1, MLLT1, and MLLT3—which encode proteins regulating epigenetic mechanisms. The presence of distinct KMT2A rearrangements is an independent dismal prognostic factor, while very few KMT2A rearrangements display either a good or intermediate outcome. KMT2A-rearranged (KMT2A-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5–6% of pediatric cases, and 15% of adult cases. KMT2A-rearranged (KMT2A-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with KMT2A ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of KMT2A-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder with variable clinical presentation. In cases where traditional diagnostic tools such as transmission electron microscopy (TEM) or nasal nitric oxide (nNO) measurement are inconclusive/unavailable, molecular diagnostics via whole-exome sequencing (WES) may provide essential insights. In this case report, we present two male infants with diverse phenotypes and genotypes. 1st patient was ultimately diagnosed with PCD thanks to WES, while 2nd patient was strongly suggestive of PCD. The 1st patient portrayed in his clinical history symptoms such as perinatal respiratory distress, situs inversus, and recurrent otitis media. He was found to carry a known pathogenic homozygous variant c.461A>C (p.His154Pro), in the CCDC103 gene. The second patient exhibited more complex phenotype, including diaphragmatic hernia, absence of the pericardium, significant delay in the motor development. WES identified two variants in both DNAH5 and DNAH9. Parental testing identified the maternal origin for the c.10243-6C>T (p.?) and c.308del (p.Phe103Serfs*31) variants in the DNAH9 gene and a paternal origin for the c.1206T>A (p.Asn402Lys) variant in the DNAH5 gene. The second variant c.5124G>T (p.Glu1708Asp) in the DNAH5 gene in the proband arose de novo. At the time of analysis, these variants were classified as variants of uncertain significance (VUS) or likely benign, with limited segregation data and no definitive functional validation. Although the genetic findings were not diagnostic on their own, the clinical picture (situs inversus, neonatal respiratory distress, recurrent infections) was strongly suggestive of PCD. Both cases illustrate the crucial role of WES in establishing a molecular diagnosis of PCD, particularly when the use of traditional diagnostic methods is inconclusive. Moreover, they demonstrate the value of genomic testing in guiding the clinical management and informing about prognosis in diseases like PCD.