De novo mutations in PURA are associated with hypotonia and developmental delay

Abstract

PURA is the leading candidate gene responsible for the developmental phenotype in the 5q31.3 microdeletion syndrome. De novo mutations in PURA were recently reported in 15 individuals with developmental features similar to the 5q31.3 microdeletion syndrome. Here we describe six unrelated children who were identified by clinical whole-exome sequencing (WES) to have novel de novo variants in PURA with a similar phenotype of hypotonia and developmental delay and frequently associated with seizures. The protein Purα (encoded by PURA) is involved in neuronal proliferation, dendrite maturation, and the transport of mRNA to translation sites during neuronal development. Mutations in PURA may alter normal brain development and impair neuronal function, leading to developmental delay and the seizures observed in patients with mutations in PURA.

Keywords: central hypotonia; generalized clonic seizures; generalized tonic seizures; severe global developmental delay.

Figure 1.

Photographs of patients. (A,B) Patient 1. (C) Patient 2. (D,E) Patient 3. (F) Patient 4. (G,H) Patient 6. Patients 1 and 2 exhibit dolichocephaly and Patients 1–5 all have a broad forehead. Note hypertelorism and highly arched palate in Patient 1 and epicanthal folds in Patient 4.

Figure 2.

Mutations in PURA. (A) Diagram of Purα with mutations identified in our patients in green. Previously identified mutations are in orange (Hunt et al. 2014; Lalani et al. 2014). Missense and in-frame deletion mutations are shown below the protein diagram and gene disrupting truncating mutations are shown above. (B) Sequence alignment of Ile188 in PUR II region illustrating conservation of amino acids at amino acid 188.