“These discoveries establish a new class of genetic disorders related to small nuclear RNA genes,” said Ernest Turro, PhD, senior author of the three studies. “Despite their comparatively high prevalence, the underlying causes of the three disorders remained unknown for years, partly because most previous studies of NDDs sequenced protein-coding genes but omitted noncoding genes. Our statistical analysis of whole-genome sequencing from NDD patients eliminated these important knowledge gaps. A critical next step is to deliver diagnoses to affected individuals who previously received negative genetic testing results."

RNU4-2 and RNU2-2 encode paralogs of RNA components of the major spliceosome, a molecular complex responsible for removing introns from precursor messenger RNA. Although disruption of splicing has long been recognized as a cause of human disease, pathogenic variants in major spliceosomal RNA genes and their paralogs were previously unknown.

The initial discovery tied variants in RNU4-2 to an NDD now known as ReNU syndrome. Subsequent work identified variants in a related gene, RNU2-2, as the cause of an NDD now known as dominant ReNU2 syndrome. Patients with each of these dominant conditions have normal expression levels of the two genes. The latest effort demonstrated that a recessive form of ReNU2 syndrome also exists, in which affected patients have a substantial reduction in the RNA encoded by RNU2-2.

“Many individuals with neurodevelopmental disorders remain without a molecular diagnosis despite extensive genetic testing,” said Daniel Greene, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai and first author of the three studies. “The identification of genetic defects associated with these disorders provides answers for affected families and points to potential paths towards therapeutic development.”

The discoveries were enabled by the analysis of large-scale genomic datasets, particularly from the National Genomics Research Library managed by Genomics England, and collaborations with researchers in England, Belgium, the Netherlands, Spain, and the United States.

The Mount Sinai researchers have also established the INDEED study, which is enrolling families to improve diagnoses, understand the natural courses of the conditions, develop clinical management guidelines, and acquire biospecimens for mechanistic studies, all of which they hope will lay a foundation for future trials.

“We are committed to partnering closely with families and referring clinicians to advance care, research, and trial readiness for these conditions,” said Mafalda Barbosa, MD, PhD, who co-leads the INDEED study with Dr. Turro. “Through our natural history and mechanistic research efforts, we hope to better understand ReNU and ReNU2 syndromes and support the development of future therapeutic approaches.”