RT Journal Article
SR Electronic
T1 <em>Profilin1</em> E117G is a moderate risk factor for amyotrophic lateral sclerosis
JF Journal of Neurology, Neurosurgery &amp; Psychiatry
JO J Neurol Neurosurg Psychiatry
FD BMJ Publishing Group Ltd
SP 506
OP 508
DO 10.1136/jnnp-2013-306761
VO 85
IS 5
A1 Pietro Fratta
A1 James Charnock
A1 Toby Collins
A1 Anny Devoy
A1 Robin Howard
A1 Andrea Malaspina
A1 Richard Orrell
A1 Katie Sidle
A1 Jan Clarke
A1 Maryam Shoai
A1 Ching-hua Lu
A1 John Hardy
A1 Vincent Plagnol
A1 Elizabeth M C Fisher
YR 2014
UL http://jnnp.bmj.com/content/85/5/506.abstract
AB Background Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders that share significant clinical, pathological and genetic overlap and are considered to represent different ends of a common disease spectrum. Mutations in Profilin1 have recently been described as a rare cause of familial ALS. The PFN1 E117G missense variant has been described in familial and sporadic cases, and also found in controls, casting doubt on its pathogenicity. Interpretation of such variants represents a significant clinical-genetics challenge. Objective and results Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1 E117G. Together, our cohorts add up to 5118 ALS and FTD cases and 13 089 controls. We estimate a frequency of E117G of 0.11% in controls and 0.25% in cases. Estimated odds after population stratification is 2.44 (95% CI 1.048 to ∞, Mantel-Haenszel test p=0.036). Conclusions Our results show an association between E117G and ALS, with a moderate effect size.