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Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC., Competing Interests: Competing interests: D.H. reports consulting and research funding from BMS, Ipsen, Novartis, Pfizer, Merck, Eisai and EMD Serono. P.M. reports honoraria for service on a scientific advisory board for Mirati Therapeutics, BMS and Exelixis, consulting for Axiom Healthcare Strategies, nonbranded educational programs supported by Exelixis and Pfizer and research funding for clinical trials from Takeda, BMS, Mirati Therapeutics, Gateway for Cancer Research and the University of Texas MD Anderson Cancer Center. S.S. reports commercial research grants from BMS, AstraZeneca, Exelixis and Novartis, is a consultant or advisory board member for Merck, AstraZeneca, BMS, CRISPR Therapeutics AG, AACR and NCI, receives royalties from Biogenex and mentors several non-US citizens on research projects with potential funding (in part) from non-US sources or foreign components. E.V.A. reports advisory or consulting roles for Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics and Serinus Bio, research support from Novartis, BMS and Sanofi, equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics and Serinus Bio, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation, intermittent legal consulting on patents for Foaley & Hoag and editorial board membership for JCO Precision Oncology and Science Advances. T.K.C. reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy and/or honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date and CME events (Peerview, OncLive, MJH, CCO and others) outside the submitted work, institutional patents filed on molecular alterations and immunotherapy response/toxicity and ctDNA, equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse and InnDura, committee membership for NCCN, GU Steering Committee, ASCO/ESMO, ACCRU and KidneyCan, potential medical writing and editorial assistance support funded by communications companies and mentorship of several non-US citizens on research projects with potential funding (in part) from non-US sources or foreign components. Dana-Farber Cancer Institute may have received additional independent funding from drug companies and/or royalties potentially involved in research around the subject matter. D.A.B. reports honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, consulting fees from Merck and Elephas, equity in Elephas, Fortress Biotech (subsidiary) and CurIOS Therapeutics, personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, Accolade 2nd.MD, DLA Piper and Merck and research support from Exelixis and AstraZeneca outside of the submitted work. S.A.S. has equity in Agenus, Agios Pharmaceuticals, Breakbio, BMS, Imunon, Jivanu Therapeutics and Lumos Pharma and receives consulting fees from Imunon and Jivanu Therapeutics. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD., Competing Interests: Declaration of interests At the time of this study and its publication, S.W.S. served on the scientific advisory committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations. S.V.M. is an employee of GeneDx, LLC. H.F.P. is on the research advisory boards and speaker bureau for Takeda Pharmaceutical, AvroBio, Amicus Therapeutics, Sanofi, Alexion Therapeutics, Denali Therapeutics, and Acer Therapeutics., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)