Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability

Original research article by D. Hunt et al. (2014).

Read the article here.

Ranging from age 4 to age 14, Hunt and colleagues reported that all four people experienced delay in developmental milestones (walking unsupported, first words, etc.), issues with motor skills, behavioral problems, and differences in facial features. Three of the four people experienced neonatal hypotonia and feeding issues, and two of the four are reported to have endocrine-related symptoms (involving the secretion of hormones in the body). Further clinical observations of the four people are summarized below.

While all four people have some similar or overlapping features, the features are common among people without PURA gene changes as well. Findings like hypotonia, speech/language delays, and motor delays are called nonspecific. From this study, it’s clear that there are not unique, diagnostic clues that can point a clinician to a diagnosis of PURA based only on physical examination and medical history. Thus, most people with PURA gene changes will be identified through whole exome sequencing or through gene panels with a focus on genes related to developmental delay. Through research like this, we are learning about the natural history of PURA gene changes and discovering that features can be variable from child to child.

The Deciphering Developmental Disorders (DDD) study in the United Kingdom uses gene sequencing to identify rare genetic changes in children who have severe, sporadic, and undiagnosed developmental delay. This paper reports on four people (three identified through DDD and one through a similar sequencing study), who have a de novo gene change (a change not found in either parent) in the PURA gene. The PURA gene plays an important role in brain development; and while clinical observations and diagnoses vary, developmental delay and learning disabilities are very common in people with a change in PURA. Hypotonia (muscle weakness), feeding difficulties, and seizures are also commonly observed.

Patient 1 Patient 2 Patient 3 Patient 4
Background Information
Age at last assessment 4y, 7mo 14y, 3mo 12y, 10mo 6y, 9mo
Sex Female Female Female Female
Neonatal hypotonia Y Y Y Y
Neonatal feeding difficulties Y Y Y Y
Developmental Milestones
Sitting unsupported (age) 2y, 6mo 1y 1y, 1mo N/A
Walking independently (age) N/A 2y 1y, 10mo N/A
First words (age) N/A 2y, 6mo 3y, 6mo 11mo
Current Developmental Level
Motor Skills Unable to stand Fully mobile Ataxia (coordination issues) Hypotonia; Dystonia (involuntary muscle spasms); Dyskinesia (impaired voluntary movement)
Language Skills No expressive language Limited vocabulary Short phrases; Repetitive; difficult to understand; limited comprehension Essentially non-verbal
Behavior Patterns N/A 2y, 6mo 3y, 6mo 11mo
Neurological Symptoms
Coordination Poor Poor Poor Poor
Gait Non-ambulatory Broad-based Broad-based Non-ambulatory
Seizures or “seizure-like” episodes Episodes at 7mo N/A Episodes at 3y Epilepsy at 14mo
Investigation
Brain MRI Delayed myelination (3y, 5mo) Normal (7y, 8mo) Normal (10y, 3mo) Multiple abnormalities
EEG Normal N/A Abnormal Abnormal
Other Features
Facial Features Hypotonic, prominent forehead, epicanthic folds (folds in skin of eyelid), mild telecanthus (increase in distance between eyes) Hypotonic, microcephaly (smaller than normal head), tall forehead, asymmetry, upslanted eyes, teeth abnormalities Slightly long face and full cheeks, high forehead, telecanthus Hypotonic, prominent forehead, thin upper lip, teeth abnormalities
Endocrine-Related Symptoms Early puberty N/A N/A Abnormal/impaired hormone function; chronically low vitamin D levels