Duplication of the Xq27.3–q28 region, including the FMR1 gene, in an X‐linked hypogonadism, gynecomastia, intellectual disability, short stature, and obesity syndrome

Abstract

In 1979 a "new" syndrome characterized by X-linked inheritance, hypogonadism, gynecomastia, intellectual disability, obesity, and short stature was described. The now-36-year-old propositus was recently referred to the genetics clinic for profound intellectual disability. Fragile X testing initially demonstrated a duplication of the FMR1 region, and upon further testing we identified an Xq27.3-q28 8.05 Mb-long duplication responsible for a syndrome. Our report describes the molecular and clinical aspects of the X-linked syndrome. Our results suggest that male patients with intellectual disability, hypogonadism, short stature, and gynecomastia should be further investigated for rearrangements in the Xq27.3-q28 region. In the future, when more cases of the duplication are identified, it may become possible to more accurately determine the specific genes affected by overexpression and responsible for the phenotype.

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…A new mouse model, the conditionally tagged FMRP-AcGFP ("cTAG") mouse, was designed to enable cell-type-specific FMRP CLIP experiments, something not previously possible in vivo. Evidence suggests that the expression levels of FMRP are tightly controlled during development, differentiation, and in response to synaptic activity, and that overexpression in humans [56][57][58][59] and model organisms 60,61 leads to negative phenotypes. Therefore, we chose a knock-in strategy to allow cell-type-specific expression of FMRP-AcGFP without altering the normal levels, splicing or regulated expression of FMRP.…”

“…Human genomic copy number variations reveal that overexpression of FMRP results in intellectual disability [56][57][58][59] , suggesting that the properties of endogenous FMRP expression should not be altered in a model system. To this end we designed a knock-in construct to result in AcGFP tagged-FMRP expression from the endogenous Fmr1 locus in a Cre-dependent manner.…”

“…It cannot be stated enough how important it is to avoid altering the timing or levels of experimentally tagged FMRP. In addition to years of literature in the field attesting to the deleterious effects of both under-and over-expression of FMRP in many system there are multiple reports of human intellectual disability linked to overexpression of FMRP due to genomic copy number variations [56][57][58][59]112 . Moreover, the interactions of RNA binding proteins with their RNA ligands are highly dependent on the relative stoichiometry between all possible binding partners.…”

FMRP Regulates Neurogenesis In Vivo in Xenopus laevis Tadpoles

“…Evidence from humans suggests that the gene dosage of FMR1 is tightly regulated and that both decreases and increases in FMRP can cause disease. Individuals with decreases in FMRP with Fragile X Syndrome and individuals with gene duplications of FMR1 both present with intellectual disability ( Rio et al, 2010 ; Nagamani et al, 2012 ; Vengoechea et al, 2012 ; Hickey et al, 2013 ). To test whether FMRP regulates cell proliferation and/or survival in the optic tectum, we manipulated FMRP expression levels using knockdown and overexpression.…”

Mapping the landscape of tandem repeat variability by targeted long read single molecule sequencing in familial X-linked intellectual disability

“…We captured and sequenced more than 1800 tandem repeats in three families with idiopathic XLID and demonstrate the feasibility of single molecule sequencing to accurately detect and size tandem repeats and tandem repeat variability. Moreover, in one family a tandem repeat expansion segregating with ID seems to affect the expression of the nearby MIR222 gene, previously implicated in ID [42] and affecting expression levels of genes associated with ID [43–46].…”