TY  - CHAP
M1  - Book, Section
TI  - The Fragile X Syndrome
A1  - Warren, Stephen T.
A1  - Sherman, Stephanie L.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Fragile  X  syndrome  (MIM  309550)  is  an  X-linked  dominant  disorder  with  reduced  penetrance.  Although  not  as  frequent  as  once  believed,  the  syndrome  remains  a  relatively  common  form  of  inherited  mental  retardation.  The  syndrome  typically  presents  in  males  with  moderate  mental  retardation,  characteristic,  but  subtle,  facial  features  of  a  prominent  jaw  and  large  ears,  and  macroorchidism  after  puberty.  Penetrant  females  are  typically  less  severely  affected.Fragile  X  syndrome  derives  its  name  from  a  characteristic  fragile  site  at  Xq27.3  that  is  found  in  a  proportion  of  chromosomes  in  metaphase  spreads  from  appropriately  cultured  cells  of  affected  males  and  many  penetrant  females.  Coincident  with  this  fragile  site,  is  a  CGG  repeat  within  the  5′-untranslated  region  (UTR)  of  the  fragile  X  mental  retardation  gene  1  (FMR1)  (GenBank  L29074).  Among  normal  individuals,  the  FMR1  repeat  is  polymorphic  in  length  and  content,  often  punctuated  by  AGG  interruptions.  The  most  frequent  normal  allele  in  Caucasians  contains  30  repeats  and  2  AGG  interruptions  at  positions  10  and  20.  In  affected  individuals,  this  repeat  is  expanded  over  230  repeats,  with  a  mean  of  approximately  780  repeats.  Thus,  fragile  X  syndrome  is  among  a  unique  class  of  human  disorders  resulting  from  unstable  repeats,  which  are  referred  to  as  dynamic  mutations.  When  the  FMR1  repeat  is  expanded  to  this  degree,  the  FMR1  gene  becomes  hypermethylated  and  transcriptionally  silent.  This  is  referred  to  as  the  full  mutation  to  distinguish  it  from  the  premutation  allele.  Premutation  alleles  are  found  in  nonpenetrant  male  carriers  and  many  female  carriers.  The  length  of  these  alleles  falls  between  that  of  the  normal  repeats  and  full  mutations.  Premutation  alleles  are  exquisitely  unstable  upon  transmission  and  the  progression  to  the  full  mutation  in  offspring  is  dependent  upon  the  length  of  the  maternal  premutation.  This  relationship  explains  the  unusual  inheritance  patterns  and  the  reduced  penetrance  of  this  disorder.Fragile  X  syndrome  is  found  among  all  ethnic  groups  studied.  The  prevalence  in  the  general  population  is  approximately  1/4500  males.  Only  50  percent  of  females  carrying  the  full  mutation  are  penetrant,  due  to  random  X-inactivation.  Because  females  only  inherit  maternal  full  mutations,  the  expected  female  prevalence  is  1/9000.  Premutation  carriers  are  found  in  approximately  1/400  females  and  1/1000  males.Molecular  laboratory  diagnosis  has  now  superseded  cytogenetic  testing  for  the  fragile  site,  although  routine  karyotype  analysis  remains  indicated  in  all  cases  of  undiagnosed  mental  retardation.  Molecular  diagnostics  routinely  involve  Southern  blot  studies,  which  provide  information  on  the  repeat  length  and  methylation  status.  PCR  studies  can  more  accurately  size  normal  and  premutation  alleles  and,  in  some  laboratories,  can  provide  an  initial  screen  for  full  mutations.  Antibody  detection  of  the  FMR1  -encoded  protein,  Fragile  X  mental  retardation  protein  (FMRP),  is  often  a  very  useful  test  as  the  lack  of  FMRP  is  the  cause  of  this  syndrome.  Indeed,  a  small  but  significant  class  of  patients  owe  their  disease  to  more  typical  mutations,  such  as  deletions,  which  all  predict  null  alleles.  Significantly,  missense  mutations  appear  markedly  infrequent,  with  the  single  exception  of  severely  affected  patients  with  a  I304N  mutation.  Protein  studies  can  be  carried  out  quickly  and  inexpensively  by  a  histochemical  analysis  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - ommbid.mhmedical.com/content.aspx?aid=1181419014
ER  -