Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, molecular pathologist, Sonic Healthcare USA, Rye Brook, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Use of long-read genome sequencing to detect and interpret variants in autism
June 2026—Studies of genetic variants in autism spectrum disorders have identified copy-number variants and single-nucleotide variants in more than 100 autism spectrum disorder-associated genes. However, much of the genetic and neurobiological bases of such disorders are still unclear. Some of the yet unexplained genetic basis of autism spectrum disorder (ASD) may lie in variants that may be difficult to detect by short-read whole genome sequencing (SR-WGS), such as specific structural variants and tandem repeats. Given that long-read whole genome sequencing (LR-WGS) has demonstrated advantages over SR-WGS in detecting structural variants and tandem repeats, the authors performed LR-WGS on 267 people from 63 families in which at least one offspring had ASD and compared the data with previously published SR-WGS data from the same cohort. They found that LR-WGS increased detection of gene-disrupting structural variants and tandem repeats, including novel exonic de novo germline and somatic variants, by 33 and 38 percent, respectively. The majority of coding structural variants were identified by SR-WGS, but LR-WGS allowed detection of a broader spectrum of small and complex structural variants. The authors also identified de novo structural variants that were not detected in a previous study of this same cohort, including a mosaic duplication event within STK33 that occurred on the maternal haplotype by phased long-read sequencing. Furthermore, they found a previously unreported class of complex duplication-deletion rearrangements (DUP-DEL), including a DUP-DEL event resulting in loss of function of CDC42BPA. Joint analysis of phased genetic variation and DNA methylation detected loss-of-function variants in imprinted genes, such as ADNP2, and demonstrated the effect of intermediate tandem repeat expansions on methylation of the FMR1 promoter. Combined, the rare structural variants, tandem repeats, and damaging structural variants accounted for 7.4 percent (95 percent confidence interval, 2.7–17 percent) of the heritability of ASD. This study uncovered additional genetic events underlying ASD and highlighted the utility of LR-WGS in identifying genetic variants that might be missed by the more commonly utilized SR-WGS. While LR-WGS identified many variants not detected by SR-WGS, it is worth noting that many genetic events that were identified by SR-WGS were not detected by LR-WGS. The authors acknowledged that given the study’s modest sample size and limited statistical power, future studies involving larger cohorts and deeper sequencing coverage may provide additional insight into the heritability and genetic variants of ASD.
Mortazavi M, Guevara J, Diaz J, et al. Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism. Cell Genom. 2026. doi.org/10.1016/j.xgen.2026.101186
Correspondence: Dr. Jonathan Sebat at jsebat@ucsd.edu
Comprehensive molecular and functional analysis of NUTM1-rearranged leukemia
NUTM1-rearranged precursor B-cell acute lymphoblastic leukemia (NUTM1-r B-ALL) has emerged as a distinct entity that is particularly relevant in infant and pediatric populations. NUTM1-r B-ALL accounts for almost 22 percent of KMT2A-germline (or KMT2A wild-type) infant B-ALL cases, with an estimated frequency of three to five percent in infant B-ALL and 0.4 to 0.9 percent in older children with B-ALL. However, the exact mechanisms of leukemic transformation of this entity are not completely understood. The authors conducted a study in which they analyzed samples from eight infants with KMT2A-germline leukemia, using RNA sequencing to identify four patients harboring a NUTM1 rearrangement (including the partner genes BRD9, AFF1, and CHD9). Targeted deep sequencing with a custom panel for infant ALL identified RAS pathway mutations in two of four patients with NUTM1-r. The authors compared RNA-seq and DNA methylation analysis data for the four NUTM1-r patients to previously published RNA-seq and DNA methylation data sets on pediatric and infant B-ALL. Notably, RNA-seq and DNA methylation analysis demonstrated that NUTM1-r leukemia constitutes a distinct subgroup with unique transcriptional and epigenetic profiling characterized by overexpression of NUTM1, low expression of CD34, and high expression of B-cell development-related genes. On differential methylation analysis, NUTM1-r leukemia was also characterized by global DNA hypomethylation. Functional analysis of NUTM1 fusions demonstrated a drive toward the B-lymphoid lineage and potent leukemic stem cell properties. The representative fusion BRD9-NUTM1 immortalized hematopoietic cells in vitro and induced leukemia in murine models. In contrast to the relative resistance observed in KMT2A-rearranged leukemia, NUTM1-r leukemic cells exhibited a robust response to cytarabine therapy, a vulnerability that may be mechanistically linked to the leukemia’s dependence on active transcription. While the study was limited to a few cases and partner genes, the findings provide further insight into the unique molecular profile of NUTM1-r leukemia and offer plausible explanations regarding the observed favorable outcomes and therapeutic vulnerabilities. Additional studies involving larger cohorts may yield further information and allow more precise risk stratification and more refined therapeutic strategies for NUTM1-r leukemia.
Nishimura K, Isobe T, Shigehiro T, et al. Comprehensive molecular and functional analysis of NUTM1-rearranged leukemia. Blood. 2026;147(13):1395–1411.
Correspondence: Dr. Masatoshi Takagi at mtakagi.ped@tmd.ac.jp or Dr. Daichi Inoue at inoue.daichi.med@osaka-u.ac.jp