Inherited PURA Pathogenic Variant Associated With a Mild Neurodevelopmental Disorder

Abstract

Objectives: Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in PURA cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual disability, early-onset hypotonia and hypothermia, epilepsy, feeding difficulties, movement disorders, and subtle facial dysmorphism. Speech is reportedly absent in most, but the specific linguistic phenotype is not well described.

Methods: We used genome sequencing to identify a pathogenic gene variant as part of a study of children ascertained for severe primary speech disorder in the absence of moderate or severe ID.

Results: The novel PURA c.296G>T (p.Arg99Leu) pathogenic missense variant segregated in the female proband and her affected mother. The proband had dysarthria; phonological disorder; and severe receptive and expressive language impairment, borderline intellect, attention difficulties, oropharyngeal dysmotility, and dysmorphic facial features. Her mother had dysarthria, moderate receptive language impairment, and borderline intellect. Both the proband and her mother completed mainstream schooling with classroom support.

Discussion: This is the first inherited PURA pathogenic germline variant in over 600 unrelated families documented on ClinVar or reported in the literature. PURA testing should be considered in families with primary speech disorder and borderline intellectual disability, given the specific genetic counseling implications.

Figure. Pedigree of Australian Family and Segregation of the PURA Variant

(A) The pedigree of the Australian family showing genotypes based on sequencing analyses. (B) Segregation of PURA c.296G>T (p.Arg99Leu) missense variant by Sanger sequencing. (C and D) Photographs of proband and her mother showing pointed chin and long face. (E) Ribbon model of the nucleic acid–binding domain of human PURA (PDB ID: 8CHT; amino acids 57–212; repeats I and II shown in grey and cyan, respectively). Side chains of R99 (magenta) and K97 (green) and K87 (green) are shown as sticks. The lower panel in (C) shows magnification of the region of interest. (F) The potential influence of R99 on the interaction with the nucleic acids. The figure shows the X-ray structure of Drosophila PURA (PDB ID: 5FGP; amino acids 40–183; repeats I and II shown in grey and cyan, respectively) with bound DNA (shown in pink). The amino acids involved in the direct interaction with DNA (K70 and R80) are shown as green sticks. The residue Q82 in Drosophila (green) and its human equivalent R99 (magenta) are shown as well. The position of R99 has been calculated from the superposition of the X-ray structure of human PURA on the Drosophila experimental model. The lower panel in (D) shows magnification of the region of interest.