RT Journal Article
SR Electronic
T1 Whole exome sequencing in family trios reveals <em>de novo</em> mutations in <em>PURA</em> as a cause of severe neurodevelopmental delay and learning disability
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 806
OP 813
DO 10.1136/jmedgenet-2014-102798
VO 51
IS 12
A1 Hunt, David
A1 Leventer, Richard J
A1 Simons, Cas
A1 Taft, Ryan
A1 Swoboda, Kathryn J
A1 Gawne-Cain, Mary
A1 ,
A1 Magee, Alex C
A1 Turnpenny, Peter D
A1 Baralle, Diana
YR 2014
UL http://jmg.bmj.com/content/51/12/806.abstract
AB Background De novo mutations are emerging as an important cause of neurocognitive impairment, and whole exome sequencing of case-parent trios is a powerful way of detecting them. Here, we report the findings in four such trios. Methods The Deciphering Developmental Disorders study is using whole exome sequencing in family trios to investigate children with severe, sporadic, undiagnosed developmental delay. Three of our patients were ascertained from the first 1133 children to have been investigated through this large-scale study. Case 4 was a phenotypically isolated case recruited into an undiagnosed rare disorders sequencing study. Results Protein-altering de novo mutations in PURA were identified in four subjects. They include two different frameshifts, one inframe deletion and one missense mutation. PURA encodes Pur-α, a highly conserved multifunctional protein that has an important role in normal postnatal brain development in animal models. The associated human phenotype of de novo heterozygous mutations in this gene is variable, but moderate to severe neurodevelopmental delay and learning disability are common to all. Neonatal hypotonia, early feeding difficulties and seizures, or ‘seizure-like’ movements, were also common. Additionally, it is suspected that anterior pituitary dysregulation may be within the spectrum of this disorder. Psychomotor developmental outcomes appear variable between patients, and we propose a possible genotype–phenotype correlation, with disruption of Pur repeat III resulting in a more severe phenotype. Conclusions These findings provide definitive evidence for the role of PURA in causing a variable syndrome of neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements and epilepsy in humans, and help clarify the role of PURA in the previously described 5q31.3 microdeletion phenotype.