PRUNE1-related disorder: Expanding the clinical spectrum

Area of Science:

• Genetics
• Neuroscience
• Rare Diseases

Background:

• Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) is an autosomal recessive condition.
• NMIHBA is associated with mutations in the PRUNE1 gene, with eight mutations previously reported in 13 families.

Purpose of the Study:

• To report novel PRUNE1 mutations in families with NMIHBA.
• To investigate the phenotypic spectrum of NMIHBA caused by PRUNE1 mutations.

Main Methods:

• Genetic analysis of affected individuals.
• Phenotypic characterization including clinical evaluation and brain MRI.
• Analysis of mutant PRUNE1 mRNA stability.

Main Results:

• Three PRUNE1 mutations were identified in six individuals across four families (one Caucasian, three Japanese).
• Two of the identified mutations (p.Leu18Serfs*8 and p.Cys180*) are novel.
• Patients exhibited atypical NMIHBA phenotypes, including the absence of progressive microcephaly and, in one case, macrocephaly, indicating a heterogeneous presentation.

Conclusions:

• PRUNE1 mutations are a cause of NMIHBA.
• The phenotypic spectrum of NMIHBA associated with PRUNE1 mutations is broader and more heterogeneous than previously recognized.
• Mutant PRUNE1 mRNA may be subject to nonsense-mediated mRNA decay.