Horrible Mutations

 Ehlers-Danlos  Autosomal  recessive

Extreme  fragility  of  the  skin,  other  symptoms  include  blue sclerae  and  soft,  velvety,  hyperextensible  skin.  Marked  bruising  and  open  wounds following  minor  trauma,  the  excised  skin  can  be  torn  by  hand.   Epidemiology: The  disease  has  been  diagnosed  among  in  several  Ashkenazi  Jewish  families  In  one family  in  which  the  origin  was  determined  the  grand  parents  were  from  Belarus Molecular  genetics: ADAMTS2    gene  (chromosomal  locus  5q23)   Homozygozity  for  the  same  mutation  [Q225X]  was  found  in  all  the  Ashkenazi  Jewish patients.  Wiki says life expectancy is normal. Pic.: The wiki, from Premalatha S, Sarveswari et al. 

Fragile  X  syndrome 

94 X linked  dominant FMR1 gene  (chromosomal  locus  Xq27)   The  disorder  is  caused  by  the  absence  of  the  FMR1  product,  almost  always  as  a  result of  a  CGG  repeat  unit  amplification  (>  200  repeats),  rarely  because  of  a  mutation  in  the gene.   Epidemiology: Among    the  cases  of  fragile  X  syndrome  in  Israel  published  in  1997  it  was  apparent that  the  disorder  is  relatively  frequent  among  Jews  of  Tunisian  origin.  In  the  136 pedigrees  surveyed  at  the  time,  36  (26.4%)  were  of  Tunisian  Jewish  origin.  In  a  Tunisian  Jewish  control  group  4  were  carriers  of  the  fragile  X  mutation (3  premutation,  one  full  mutation).  Studying  the  Tunisian  Jewish  chromosomes  with the  mutation,  there  was  an  unusually  high  proportion  (20%)  that  completely  devoid AGG interruption.  The  largest  of  these  uninterrupted  alleles  was  found  on  a  unique haplotypes  suggesting  a  founder  effect  that  may  be  originating  from  the  Island  of Djerba. In  several  screening  programs  performed  among  Jews  in  Israel  the  incidence  of  the disorder  was  found  to  be  1:3000.  The  carrier  frequency  (more  55  repeats)  was approximately  1:150.  

From the wiki: Fragile X syndrome has traditionally been considered an X-linked recessive condition with variable expressivity and possibly reduced penetrance.^[12] However, due to genetic anticipation and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labeling X-linked disorders as dominant or recessive.^[40] Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation.^{[citation needed]}

Before the FMR1 gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that genetic anticipation was occurring.^[13] This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985.^[13][41] Due to this, male children often have a greater degree of symptoms than their mothers.^[42]

The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm.^[13][29] Incidentally, males with a full mutation only pass on premutations to their daughters.^[29] However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected.^[29][36] In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. Repeat expansion is considered to be a consequence of strand slippage either during DNA replication or DNA repair synthesis.^[43]

 Samaritan  myopathy

 Autosomal  recessive. In  contrast  to  other  congenital  myopathies  where  muscle  weakness  is  progressive  or stable  the  benign  Samaritan  congenital  myopathy  is  characterized  by  an  ‘‘inverse’’ course  of  disease.  The  patients  are  severely  affected  at  birth  and  improve  progressively being  minimally  affected  at  adult  stage.   Epidemiology  and  Molecular  genetics: RYR1  gene  (chromosomal  locus  19q13.1) The  diaese  was  reported  in  one  Samaritan  family  in  which  the  patients  were homozygous  for  c.3263A>G  (p.Tyr1088Cys).    The  Samaritans  are  an  ethno-religious group  of  741  people  living  in  Israel  and  Nablus.  Ancestrally,  they  consider  themselves as  descendants  of  the  10  lost  tribes  that  formed  the  Kingdom  of  Israel.  The  Samaritan population  has  the  highest  recorded  inbreeding  coefficient  in  human  populations  due to  almost  exclusive  intra-lineage  marriages.