Germline de novo alterations of RUNX1T1 in individuals with neurodevelopmental and congenital anomalies
Erfan Aref-Eshghi,
Katherine J. Anderson,
Lauren Boulay,
Kathleen Brown,
Jessica Duis,
Christine A. Giummo,
Jessica Ogawa,
Deanna Alexis Carere,
Elizabeth A. Normand,
Yaping Qian,
Kirsty McWalter,
Erin Torti
Affiliations
Erfan Aref-Eshghi
GeneDx, LLC, Gaithersburg, MD 20877, USA
Katherine J. Anderson
University of Vermont Larner College of Medicine, Department of Pediatrics, Division of Clinical Genetics, Burlington, VT 05401, USA
Lauren Boulay
Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO 80045, USA
Kathleen Brown
Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO 80045, USA
Jessica Duis
RareDiseaseDoc, LLC, Aurora, CO, USA
Christine A. Giummo
University of Vermont Larner College of Medicine, Department of Pediatrics, Division of Clinical Genetics, Burlington, VT 05401, USA
Jessica Ogawa
Case Western Reserve University School of Medicine/Rainbow Babies and Children’s Hospital, Department of Genetics and Genome Sciences, Cleveland, OH 44106, USA
Summary: Runt-related transcription factor 1 translocated to 1 (RUNX1T1; also known as eight-twenty-one [ETO]) encodes a transcription regulator for hematopoietic genes and is well known for its involvement in hematologic malignancies, particularly acute myeloid leukemia (AML). However, its role in congenital disease is less understood. This study provides detailed clinical and molecular information on three cases exhibiting neurodevelopmental and congenital anomalies with germline de novo alterations in RUNX1T1. One case features a de novo nonsense variant in the 5′ region of the gene (c.106C>T p.Gln36Ter), while the other two harbor de novo missense variants in the C terminus end (c.1234G>A p.Gly412Arg and c.1561C>T p.His521Tyr). Common features across cases include craniofacial dysmorphism and neurodevelopmental issues, including developmental delay, learning disabilities, attention-deficit hyperactivity disorder, and autism. This study, in conjunction with previously reported germline disruptions of RUNX1T1, provides evidence supporting the role of germline RUNX1T1 variation in human congenital neurodevelopmental disorders.
