PRUNE1 c.933G>A Synonymous Variant Induces Exon 7 Skipping, Disrupts the DHHA2 Domain, and Leads to an Atypical NMIHBA Syndrome Presentation: Case Report and Review of the Literature

Authors

Christina L Magyar
David R Murdock
Lindsay C Burrage
Hongzheng Dai
Seema R Lalani
Richard A Lewis
Yuezhen Lin
Marcela F Astudillo
Jill A Rosenfeld
Alyssa A Tran
James B Gibson
Undiagnosed Diseases Network
Carlos A Bacino
Brendan H Lee
Hsiao-Tuan Chao

Publication Date

6-1-2022

Journal

American Journal of Medical Genetics Part A

DOI

10.1002/ajmg.a.62704

PMID

35194938

PMCID

PMC11149102

PubMedCentral® Posted Date

6-4-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Child, Exons, Histidine, Humans, Male, Microcephaly, Muscle Hypotonia, Pedigree, Phosphoric Monoester Hydrolases, neurodevelopmental disorder, hypotonia, spastic paraparesis, splice site variant, alternative splicing

Abstract

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.