PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Abstract

Background: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.

Objectives: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.

Methods: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.

Results: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.

Conclusion: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Keywords: PURA syndrome; epilepsy and seizures; hypotonia; intellectual disability; neonatal problems.

Figure 1

Localisation of PURA mutations and subdivision in classes. Mutations of individuals identified in our cohort are marked in bold. (A) Homology models of N-terminal and C-terminal PUR domains (grey and blue, respectively) from human Pur-alpha. Residues with single amino acid exchanges are depicted in red with side chains. (B) Location of reported PURA frameshift and non-sense mutations. Class A1 mutations are located in the N-terminal PUR domain that affect both N-terminal and C-terminal domains and class A2 mutations occur in the C-terminal domain, affecting only this domain and the C-terminus. (C) Identified point mutations in one of the PUR domains, predicted to cause local folding defects. (D) Four mutations of amino acids located on the protein surface. Three mutations are predicted to affect nucleic acid binding (class C) and one mutation (class D) likely affects a surface-exposed residue, which is not predicted to impair protein folding or nucleic acid binding. This mutation is possibly involved in not yet understood functions such as protein–protein interactions. (E) Deletion (red) caused by mutation p.(Met1?) (class E), which disrupts the start codon. The protein is likely expressed from the next in-frame start codon at amino acid 104, causing loss of a functional N-terminal PUR domain, but has an intact C-terminal PUR domain. (F) Localisation of mutations reported in healthy controls in the ExAC database. All these mutations are predicted to have no effects on the folding and the function of the Pur-alpha protein. PUR, purine-rich element.

Figure 2

Photographs of 21 individuals with PURA mutations. Shared facial dysmorphism includes high anterior hairline, almond-shaped palpebral fissures, full cheeks and hypotonic face. Strabismus is present in several of the PURA (purine-rich element binding protein A) individuals. Additionally, independent dysmorphologists also observed eversion of lower lateral eyelids, prominent, well-defined philtrum and retrognathia in a subset of the individuals.

Figure 3

Computational analysis of photographs of PURA (purine-rich element binding protein A) syndrome individuals. Result of an objective computational analysis on photographs of 34 individuals with PURA mutations (ages at photographs ranging from 2 months to 19 years; right image) compared with the average image based on 301 age-matched, healthy controls (left image). The computational modelled PURA face showed a hypotonic face with typically open mouth appearance and full cheeks. Additionally, two independent dysmorphologists reported a slightly abnormal shape of the eyes as (1) shorter palpebral fissures and (2) eversion of lower lateral eyelids. The high anterior hairline observed in a subset of individuals is not visible on this computational model of the PURA face.