Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Am J Med Genet A. 2024 Jun;194(6):e63548. doi: 10.1002/ajmg.a.63548. Epub 2024 Jan 24.

Abstract

Pathogenic PHF21A variation causes PHF21A-related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability and overgrowth and a novel de novo heterozygous PHF21A splice variant (NM_001352027.3:c.[153+1G>C];[=]) causing skipping of exon 6, which encodes an in-frame BHC80 deletion (p.(Asn30_Gln51del)). This deletion disrupts a predicted leucine zipper domain and implicates this domain in BHC80 function and as a target of variation causing PHF21A-related NDDs. This extension of understanding emphasizes the application of RNA analysis in precision genomic medicine practice.

Keywords: ID (intellectual disability); PHF21A (plant homeodomain finger protein 21A); RNA splicing; overgrowth; transcriptome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Child
  • Exons / genetics
  • Female
  • Humans
  • Intellectual Disability* / genetics
  • Intellectual Disability* / pathology
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / pathology
  • RNA Splicing* / genetics
  • Sequence Analysis, RNA