Prune exopolyphosphatase-1 (PRUNE1) encodes a member of the aspartic acid–histidine–histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss-of-function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1-related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous PRUNE1 NM_021222.2:c.933G>A synonymous variant identified in a 6-year-old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the PRUNE1 NM_021222.1:c.933G>A variant resulted in an in-frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH-associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in PRUNE1-related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations.

Original languageEnglish
Pages (from-to)1868-1874
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Issue number6
StatePublished - Jun 2022


  • alternative splicing
  • hypotonia
  • neurodevelopmental disorder
  • spastic paraparesis
  • splice site variant


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