Genetics (week 5): Autosomal Recessive
Aa = unaffected "carrier", v common status
AA = unaffected
aa = affected
autosomal recessive allele
travels silently through families
only an affected individual when two carriers mate
horizontal look to pedigree: affected individuals from normal parents
recurrent risk of 25% in sibship w/o regard to gender
if abn is rare one often finds consanguinity in pedigree-->affected offspring
affected mates with normal-->usu normal offspring
penetrance not a factor here
the larger the sibship the more likelihood of seeing expression (why is this?)
genetic "burden" or "load" of harmful recessive alleles: common
carrier stats:
1/50 CF
1/100 PKU
1/300 GAL
1/500 TS
1/1000 FH
number of affecteds is 25% of the square so increasingly small as fractions get smaller
PHENYLKETONURIA
OMIM 261600
autosomal recessive disorder of **amino acid metab
**accumulation of phenylalanine, can't convert to tyrosine
damages CNS, **severe mental retardation, irritable, vomiting
sx: **hypopigmentation, **unusual musty ordor (phenylactate)
12q22-q24.2, many alleic variants knkown
prog: good if txd early, rstrx diet, no aspartame, no milk, meat, nuts, special products
no mother's milk!
1/15000 affected, 1/50 are carriers (Pp)
screening test done at day 3 after birth, some false positives on test
cheaper to test than to tx later
look for consanguinity in pedigree, horizontal look: sibs affected
**odds of unaffected from carrier parents being a carrier? 2/3 (arm waving moment)
ALBINISM
OMIM 203100 for type 1
amino acid metab disorder, can't convert TYR to melanin
melanin def, photophobia, red eyes, pale skin & hair
1/40,000
gene 11q14-q21
condition is benign
affects are aa
parents of affecteds are heterozygote carriers
TAY SACHS
GM2 gangliosidosis
OMIM 272800 for infantile form
autosomal recessive lipid metabolic disorder-->accumulation of semi-degraded myelin in residual bodies of neurons and glia
lysomsomal storage dz dt failure of enz: beta-hexosaminidase
Ashkenazi Jews 1/3500, 1/30 carriers, ample consanguinity
unheard of in other pop, more like 1/350,000, 1/300 are carriers
prog: grave: child's born normal, OK first couple months, dies at age 1-5
CYSTIC FIBROSIS
OMIM 219700
autosomal recessive disorder of chloride transporter CFTR, imp in secretory cells
sx: **v salty sweat, thick resp mucus secretion-->bact growth-->resp infx
sx:**blockage of biliary tract, poor digestion, pancreatic insufficiency
1/2500 in European caucasians **not uncommon
less common in Hispanics, very uncommon in Blacks, rare in Asians
prog: better in last 30 years with better abx and resp therapy
7q31.2, up to 1000 genetic variants for this dz
sx: vas deferens doesn't form
sx: SI obstrx dt thick stool
new tx: airspray that solublizes mucus
experimental tx: using retrovirus to insert genes in resp tract mucosa, vetoed unless pt is dying
mixed results: sprayed it in and 10% of cells picked up gene and expressed it and brought them back up to just below clinical threshhold for tx, then cells affected by gene transplant died off and pt went downhill again, but 2nd tx won't work because pt is now immune to original virus......years to create
2/3 chance carrier mates with general pop 1/25 chance-->1/150 chance of affected offspring