ClinVar Genomic variation as it relates to human health

Micrognathia (present) , Osteopetrosis (present) , Failure to thrive (present) , Short stature (present) , Hypoplasia of the corpus callosum (present) , Delayed speech and language development (present) , Seizure (present) , Abnormal facial shape (present) , Hypotonia (present) , Intellectual disability (present) , Microcephaly (present) (less)

In 33 unrelated individuals with ReNU syndrome (RENU; 620851), Greene et al. (2024) identified a de novo heterozygous 1-bp insertion (n.64_65insT, NR_003137.2) in the RNU4-2 gene. The mutation, which was found by whole-genome sequencing, was not present in the gnomAD database. The G at position 64 of the gene localizes to the U4 snRNA quasi-pseudoknot that is thought to contribute to the stability of the ACAGAGA loop of U6 snRNA (see 180692), which binds 5-prime splice sites and induces splicing after U4-U6 unwinding. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the variant could disrupt splicing. In a 5.4-year-old girl, born of unrelated Dutch parents, with RENU, Schot et al. (2024) identified a de novo heterozygous n.64_65insT mutation in the RNU4-2 gene. The variant was not present in 76,215 genomes in gnomAD (v4.0). RNA-seq analysis of patient-derived fibroblasts did not show signs of large-scale intron retention. Additional functional studies were not performed. The patient was part of a cohort of 164 individuals with neurodevelopmental abnormalities who underwent whole-genome sequencing (0.61%). In 89 individuals with RENU, Chen et al. (2024) identified a heterozygous n.64insT mutation in the RUN4-2 gene. The mutation occurred de novo in all individuals from whom parental DNA was available. Moreover, the mutation occurred on the maternal allele in all 54 patients for whom the parental allele of origin could be determined. The mutation was not present in gnomAD (v4.0). RNA-seq analysis of blood samples from 3 individuals with this mutation contained more abnormal splicing events compared to 378 controls, but the difference did not reach significance. However, abnormal splicing events corresponding to increased use of unannotated 5-prime splice sites was significantly increased in mutation carriers compared to controls. Sequence motif analysis showed that the 5-prime splice site positions occurred in the region that pairs directly with the U6 ACAGAGA region during spliceosome activation. (less)

Strabismus (present) , Blindness (present) , Nystagmus (present) , Autism (present) , Seizure (present) , Failure to thrive (present) , Sleep abnormality (present) , Short stature (present) , Lower limb asymmetry (present) , Barrett esophagus (present) (less)