Fragilex

Incidence

 * ~1/3,000 males
 * ~1/8,500 females
 * 40% of X-linked ID
 * 2-6% of unexplained ID in males
 * 2-4% of unexplained ID in females
 * ID in 50% of females with full mutation; dependent on X-Inactivation
 * Carrier Frequency
 * 1/152 = Israel
 * 1/197 = USA, Minnesota
 * 1/259 = French Canadian
 * 1/561 = USA, Baltimore
 * Rare in Basque, Native American Populations

Molecular Etiology

 * Xq27
 * FMR1 = CCG repeat
 * 6-54 repeats = Normal
 * 55-200 repeats = Carriers, potential for Primary Ovarian Failure in women and FXTAS in males
 * Repeats usually expand when transmitted by mothers, not fathers
 * 200+ repeats = Fragile X Syndrome
 * 10-20% Mosaicism
 * Repeat Size Mosaicism
 * Methylation Mosaicism
 * FMRP
 * expressed in fetal and adult tissues, brain, testes
 * Fragile X-related gene family (FXR1 & FXR2P)
 * binds to 4% of brain mRNAs in vitro
 * functions as repressor of specific mRNA translation
 * oversynthesis of metabotropic glutamate receptor in absence of FMRP; alters synaptic maturation

Craniofacial Features

 * prominent jaw
 * thick nasal bridge
 * large ears

Endocrine/Growth

 * gynecomastia
 * tall stature

Musculoskeletal

 * Connective Tissue Defects
 * Mitral Valve Prolapse
 * aortic dilation
 * stria
 * hyperextensibility

Genitourinary

 * macroorchidism

Neurological

 * Autism = 7.5%
 * Intellectual Disability