Abstract
FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.
Highlights
The majority of reported FMR1 copy number variant (CNV) were deletions identified in patients who underwent clinical testing for neurological features such as developmental delays (DD), intellectual disability (ID), autism spectrum disorder (ASD), and/or epilepsy, with four small duplications only containing FMR1 (Table 1)
Pathogenic deletions involving the whole gene or eliminating c.1 were found in both male and heterozygous female probands, with presentations ranging from typical Fragile X syndrome (FXS) to nonsyndromic epilepsy
Four deletion alleles were found in individuals who were tested for reasons other than the presence of clinical manifestations
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Fragile X syndrome (FXS) is an X-linked disorder due to a loss of FMR1 function. The phenotype involves both neurological and physical features, including developmental delays (DD), intellectual disability (ID), autism spectrum disorder (ASD), attentiondeficit/hyperactivity disorder (ADHD), joint hypermobility, and characteristic facial features such as a long face, large or prominent ears, prominent forehead, and prominent jaw [1,2]. Because not all features are present in all affected individuals, FMR1 pathogenic variants can be found (or may not be recognized) in patients with apparently nonsyndromic
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