Niiiam Beinstein

!"#"$%&' )%#*+ ,"-%". /01%#2 3453

1


671898'89" 5:
Rh Bloou Antigen System RBB uene:
1. Rh+ inuiviuual:
a. Piouuces the RhB antigen on the RBC membiane
2. Rh - inuiviuual:
a. Absence of antigen on RBC membiane
S. ;"98+<$%& =%'"*'" 8> $7" ?".@81#: anti-Rh antibouies (Rh- mom) can
cioss the placenta fiom the mothei anu cause the (ih+ baby_ RBCs in the
fetus to lyse piouucing anemia that uoes not piesent until shoitly aftei biith.
671898'89" A:
Newfounulanu Recombinant:
5B C"1%&"#$1%& D#-"1'%8#
671898'89" E:
F&78#G180+*'%*:
1. AB mutation in tyiosine kinase fibioblast giowth factoi ieceptoi FuFRS
a. Noimally has a negative iegulatoiy effect on bone giowth
b. Nutation makes the ieceptoi hypeiactive!shoit bones
c. No allelic heteiogeneity, same mutation in eveiy patient
2. !*%# 8> >H#&$%8# mutation in guanine the 11S8 position
a. Nost mutable nucleotiues in human gene
b. Almost 1uu% of the mutations
S. /78.' *++"+%& 7"$"182"#"%$<: 8u% aie G" #8-8 9H$*$%8#: almost
exclusively 0*$"1#*+ 08%#$ 9H$*$%8#' I%#&1"*'"' .%$7 *2"J
a. Incieaseu inciuence with incieaseu pateinal age
b. Laige amount of BNA ieplication goes on foi the million of speim to
be piouuceu
4. Piesents with failuie of caitiliage cell piolifeiation at the giowth plates
causes ihizomella (uispiopoitionate length of the pioximal limb) small
statuie, laige heau, piominent foieheau, lumbai loiuosis, noimal intelligence
;H#$%#2$8#K' =%'"*'":
1. AB, Polyglutamine iepeat of CAu on 4p,Buntington gene in the &8G%#2
1"2%8#
2. Nutateu gene causes abnoimal inteiactions with TFs, they aie stuck to the
abnoimal gene
S. 0nuei 4u iepeats is pie-mutation!0*$"1#*+ anticipation
4. Choiea, athetosis, uystonia, loss of cognition, psychiatiic abnoimalities






671898'89" L:
61% =H 67*$:
5B ="+"$%8#M 1u-1S% of cases one paient caiiies aie iecipiocal tianslocation
*B Nostly spontaneous inheiitance
3B Chilu has a mewing ciy, low biith weight, failuie to thiive, hypotonia,
psychomotoi 1"$*1G*$%8#, 9%&18&"07*+<, hypeiteloiism (excessive wiuth
between bouy paits), iounu face, anti-mongoloiu slant of eyes, epicanthus
folu of skin of uppei eyeliu ovei innei angle of the eye, mental ietaiuation,
low-set yeai
AB Suivival into auulthoou is not common
)*9%+%*+ FG"#89*$8H' C8+<08'%' I)FCJ
4. Nutation in APC involveu in Wnt signaling pathway
S. Beta catenin levels aie uniegulateu anu accumulate, tiavel to the nucleus anu
activate tiansciiption causing cell piolifeiation anu acceleiateu tumoi
initiation
6. Polyps in the colon befoie age 2S, numbeis in the thousanus, colonectomy
may be neeueu foi pieventative measuies
671898'89" N:
68#2"#%$*+ FG1"#*+ ;<0"10+*'%*
1. AR mutation in CYP21 gene on 6p encouing foi 21-hyuioxylase
2. viiilization of female infants occuis with the excess piouuction of anuiogens
S. 46XX patients have noimal ovaiian tissue but have ambiguous genitalia
a. Enlaigeu clitoiis anu labial fusion
b. 0luei patients will unueigo masculinization uuiing pubeity alone
with a ueepening of the voice anu the appeaiance of facial haii as well
as a failuie to menstiuate
4. 46XY males can entei pubeity at ages 2-S, piecocious pubeity
671898'89" O:
6<'$%& )%@18'%':
1. Autosomal iecessive, common in noithein Euiopean populations
2. 6u% of the time is fiom a mutation in CFTR on 7q, uelta FSu8
S. NBB-1 uomain is usually affecteu.
4. Nouifiei genes:
a. NBL-2 loss of function, iesults in a woise phenotype
b. TuFbeta1 gain of function iesults in a woise phenotype incieasing the
scai tissue in the lungs
S. Biagnoseu with sweat test being oveily salty, pancieatic insufficiencies iesult
in gieasy stools anu ueficiencies in fat soluble vitamins
6. Thick mucus in the lungs iesults in pulmonaiy infections anu eventually
failuie
7. vas uefeiens aie absent in 9S% of males!infeitility




ASO
Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
S


P%++%*9K' /<#G189": Q+>%#
1. ="+"$%8# of 26 genes fiom 7q, incluues the elastin gene
2. Elfin facial appeaiance, cheeiful uemeanoi, ease with stiangeis, loves music
S. Aoitic stenosis
4. Tiansient hypeicalcemia
671898'89" R:
,"&89@%#*#$ R:
1. Inveision on chiomosome 8
2. Common with Bispanics in the Southwest 0S
S. Lethal conuition causeu by seveie caiuiac abnoimalities anu mental
ietaiuation
671898'89" S:
FTU T+88G !18H0 /<'$"9:
1. Fiameshift Nutations between A anu B (4 nucleotiues)
2. S alleles foi one gene
S. A anu B aie co-uominant
4. 0 is iecessive!just the B antigen anu no tiansfeiases, #H++ 9H$*$%8#
S. Tiansfusion incompatibility!hemolysis
Bloou Type uenes Antibouies Enzyme name
A AA oi A0 Anti B N-Acetyl
glucosamine glycosyl
tiansfeiase
*GG' ?V
*&"$<+2*+*&$8'*9%#"
B BB oi B0 Anti A B-galactose tiansfeiase
FGG' GV2*+*&$8'"
AB AB None 0niveisal Recipient,
both tiansfeiases
0 - iecessive
(B antigen)
00 Anti A anu
Anti B
0niveisal uonois, no
tiansfeiase

)1%"G1%&7 F$*W%*
1. AR uefect in the FRBA gene: iepeats of !FF %# $7" >%1'$ %#$18# impaiiing
tiansciiptional elongation, inhibits polymeiase
a. Expansion of 1uu-12uu copies (7-S4 is noimal)
2. Nutation is in mRNA!#8#V&8G%#2 1"0"*$'!causes gene silencing thiough
inuuction of heteiochiomatin stiuctuie
S. Spinoceiebellai ataxia that manifests befoie auolescence with incooiuination
of limb movements, uifficulty with speech, caiuiomyopathy, scoliosis,
uiminisheu oi absent tenuon ieflexes anu impaiiment of position anu
vibiatoiy senses


FISH
671898'89" 55:
F&H$" D#$"19%$$"#$ C8107<1%*:
7. AB mutation in PuPB
8. 0iopoiphyiinogen I synthasePBu ueaminaseBNB synthase
9. Noie females than males aie obseiveu
1u. Poiphobilinogen (PBu) anu uelta ALA accumulate in bloou!uiine
11. Piesents with acute inteimittent abuominal pain, hallucinations, uepiession,
anxiety, seizuies, aiihythmias, #8 078$8'"#'%-%$<
12. Tiiggeieu by: baibituates, steioius, catabolic uiet, suigeiy
1S. Beme level is uecieasing because moie cytochiome p4Su enzymes aie being
piouuceu
T"&X.%$7VP%"G9*#:
1. 0nipaiental uisomy foi ain impiinteu poition of chiomosome 11p
2. Incluues IuF-2 ! Cieates big babies
S. Nacioglossia
4. Seveie hypoglycemia
S. Nalignant neoplasms of the kiuney, auienal glanus, anu livei
6. 0mphalocele: Intestines oi abuominal oigans aie piesent outsiue of the bouy
at biith.
T"$* Y7*+*''"9%*:
1. 2 copies of the beta globin gene, mutations aie uue to single-base-paii
substitutions!08%#$ 9H$*$%8#'
2. Piesents 3 $8 N 98#$7' *>$"1 @%1$7 when fetal gamma globin is conveiteu to
auult beta globin
S. Bu Allele: no BbA piesent
a. Complex: laige ueletions that can iesult in an absence of beta globin
4. B+ Allele: 1u-Su% of BbA is uetectable
a. You neeu 2 beta chains to foim BbA2!less is piouuceu
b. Simple: ueciease in the abunuance of beta globin
i. Nutations in the mRNA such as splicing, piomotei mutants,
capping, fiameshift mutations, nonsense mutations (tiuncateu
beta globin)
S. Y7*+*''"9%* Z%#81: Caiiieis with one mutateu allele
a. uenotype of B+B oi BuB, Niciocytic anemia
b. Lowei than noimal NCv value, inciease in the fiaction of BbA2 anu a
ueciease in the fiaction of BbA
6. Y7*+*''"9%* Z*[81 \688+"<K' =%'"*'" when both copies have no function
oi aie missing
a. uenotype of B+Bu oi BuBu oi B+B+
b. Toxic inclusions ieuuce RBC lifespan, seveie hemolytic anemia,
chipmunk faces, fiactuies, teaiuiop cells, hypochiomia anu
miciocytosis
c. 0piegulation of BbF anu BbA2 occui because theie isn't enough BbA
u. Beath will occui in chiluhoou if not tieateu with tiansfusions, iion
chelation anu splenectomy, bone maiiow tiansplant can cuie.
Port wine colored
Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
S


;"982+8@%# 6 =%'"*'" I;@6J
1. AR mutation position 6: ulu!Lys
2. Tenus to &1<'$*+%]"M less soluble than BbA, milu anemia,
;"982+8@%# ;*99"1'9%$7:
1. AB mutation in beta chain E3 C7"!/"1
2. 0nstable hemoglobin to be unstable causes heme to uiop out of its pocket
S. Low oxygen affinity causes cyanosis
;"982+8@%# ;<G" C*1X I;@ZJ
1. AB mutation in the beta chain 92 Bis!Tyi
2. Nethemoglobin: oxiuizeu heme iion is %#&*0*@+" 8> 1"-"1'%@+" 8W<2"#*$%8#
S. Cyanosis in 7"$"18]<28$"'
;"982+8@%# ^"90'"<:
1. F= missense mutation 99 Asp!Asn
2. uain of Function mutation
S. Locks Bb in its high affinity oxygen stateielaxeu stiuctuie
4. Causes polycythemia: abnoimal inciease in the numbei of ciiculating RBCs
/%&X+" 6"++ =%'"*'":
1. AR tiansveision missense mutation in the 6
th
couon of beta globin ulu!val
2. Nutation causes BbS wheie the two mutant chains ieplace 2 noimal alpha
chains
S. Bemoglobin polymeiizes uuiing ueoxygenateu conuitions (T state) sticking,
causing an inflexible RBC
4. The RBCs aie also uestioyeu piematuiely causing inflexible RBC
S. Niciovasculai occlusion!ischemia, pain, oigan uamage in the spleen, CNS,
bones, livei, kiuneys anu lungs
6. Patient will have jaunuice, splenomegaly, sausage uigits, iepeateu infection
(cause of ueath) anu an Tb level of 6-1u guL
="#<'V=1*'7 /<#G189" I==/J
1. AB mutation in the WT1 gene: Wilm's tumoi suppiessoi gene on 11p
2. Causes XY males to have ambiguous exteinal genitalia
S. Bisiupts noimal testiculai uevelopment, loss of playfulness, uecieaseu
appetite, weight loss, giowth uelay, abnoimal skeletal uevelopment,
insomnia, abuominal pain, constipation, anuiia
4. Eaily nephiotic synuiome anu culminates in ienal failuie in the fiist S yeais
of life.
)1*'%"1 /<#G189"
5B Seveie AB uisease uue to mutations in the Wt1 gene on 11p
3B Chaiacteiizeu by nephiopathy, complete gonaual uysgenesis (XY female) anu
iisk of gonaual blastoma in eaily chiluhoou




ASO: detects known mutation
671898'89" 53:
D 6"++ =%'"*'":
1. AR foi the uNPTAB gene
2. Beficiency in ulcNAc phosphotiansfeiase causing mucolipiuosis
S. Nutation in piotein tiafficking: leaus to absence of mannose-6-phosphate
attachment ovei enzymes taigeteu to lysosomes
a. Enzymes will not ieach lysosomes anu be secieteu out of the cell into
the bloou stieam
4. Biagnoseu by an incieaseu level of lysosomal enzymes in plasma anu an
absence of lysosomal enzymes in the lysosomes
a. 'HG*# @+*&X T I+%0%G'J *#G CF/ I2+<&82"#J
S. Causes accumulation of glycopioteins in the cell
6. 0nusual facial featuies, seveie motoi anu cognitive ietaiuation,
kyphoscoliosis, uwaifism, &81#"*+ &+8HG%#2
7. Beath occuis in the fiist uecaue: S-7 yeais.
C*++%'$"1V^%++%*#:
1. =H0+%&*$%8# of all oi pait of chiomosome 12p
2. Results in a paitial tiisomy!mosaicism
S. Seveie mental ietaiuation, pooi muscle tone, coaise facial featuies,
piominent foieheau, thin uppei lip with a thickei lowei lip anu a shoit nose
4. Seizuies, pooi feeuing, stiff joints, cataiacts in auulthoou, heaiing loss anu
heait uefects
C7"#<+X"$8#H1%* IC^_J
1. AR, patients aie usually compounu heteiozygotes
a. Niluei mutation pieuominates foi phenotype
2. Classic: mutations both alleles of PAB gene: C7"#<+*+*#%#" 7<G18W<+*'"
S. Non-Classic: Y"$1*7<G18@%80$"1%# IT;EJ pioblems with iecycling
4. Phenylalanine can't be maue into tyiosine anu it builus up to toxic levels
S. Piesents with mental ietaiuation via uevelopmental uelay in infancy,
9%&18&"07*+<, 7"*1$ 9*+>819*$%8#, seizuies, hypeiactivity, anu behavioial
uistuibances, musky smell to uiine (phenylpyiuvate aciu)
6. Is testeu foi biith in inuustiializeu nations with a heel-piick of the
newboin
7. Chilu can be affecteu if the mothei has uncontiolleu PK0
a. CNS abnoimailities: mental ietaiuation
8. Tieateu with uiet mouification
671898'89" 5A:
Y1%'89< 5A: C*$*HK' /<#G189"
1. Nost seveie of the thiee tiisomies
2. Niciopthalmia (abnoimally small eyes)
S. Niciocephaly (mental ietaiuation)
4. Polyuactyl
S. Pienatal Testing: uecieaseu PAPPA, Becieaseu hBCu, uecieaseu 0Se
concentiation, uecieaseu inhibin A

Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
7


,"$%#8@+*'$89*
5B AB mutation in the Rb gene (tumoi suppiessoi), usually iegulates u1!S
checkpointuephosphoiylateu Rb inteiacts with E2F anu pievents E2F fiom
stimulating tiansciiption (this uoesn't happen with ietinoblastoma)
3B I= 12u,uuu, autosomal uominant
AB Founu in infants, iapiu iate of piolifeiation cieates tumois in the eyes, .7%$"
1">+"WM iemoval of eye foi tieatment, 2
nu
inciuence is a mattei of chance
671898'89" 5E:
F+07*V5VF#$%$1<0'%# =">%&%"#&<:
1. AR mutation in alpha 1 antitiypsin which inhibits elastase piouuction fiom
neutiophils
2. ` *++"+": homozygotes will have *221"2*$"' of alpha-1-antitiypsin in the
hepatocytes, tiappeu in the iough enuoplasmic ieticulum, (1S% of noimal)
a. Little alpha-1-antitiypsin is secieteu!&8#>819*$%8#*+ G%'"*'"
b. Smoking makes this woise by !"#$#%#&' )*+,#!&#&* in the active site
causing a ieuuceu affinity of the alpha-1-antitiypsin foi elastase
i. Elastase can now tiavel to the lungs anu bieakuown alveoli
walls
S. This mostly affects the lungs anu livei iesulting in emphysema anu ciiihosis
671898'89" 5L:
F#2"+9*# /<#G189":
1. S-4 Nb ueletion inheiiteu fiom mothei (46)
3B _@"AF H@%aH%$%# 018$"%# %' *>>"&$"GbH'H*++< 8#+< *&$%-" %# 9*$"1#*++<V
%#7"1%$"G &71898'89" I0*$"1#*+ 2"#" %' $H1#"G 8>> @< 2"#89%&
%901%#$%#2JB
*B 0biquitin piotein ligase
@B Taigets ARC synapses
&B Nutateu 0BSA causes an accumulation in Aic, uecieasing the
signaling of neuions, causing impaiieu neuional communication anu
synaptic uevelopment
S. "Bappy Puppets" - jeiky puppet like movements with lots of laughtei
4. Ataxic uait
S. Seizuies anu spacticity
6. Seveie uevelopment ueficit
C1*G"1VP%++% /<#G189":
1. S-4Nb ueletion inheiiteu fiom the fathei (46), pioximal poition
2. Nutation fiom the fathei
S. 1S of cases have unipaiental uisomyno copies fiom the fathei anu 2 fiom
mom
4. 0besity (love to eat!), hypogonauism, small hanus anu feet, shoit statuie




Hyperphosphorylated Rb cant bind E2F; transcription & proliferation happen
Z*1>*#K' /<#G189":
1. AB mutation in Fibiillin gene FBN1 which encoues foi the glycopiotein
fibiillin-1 which maintains elastic fibeis anu foims them in the ECF
2. 0sually binus latent TuFbeta, sequesteiing it
a. Nutation allows TuFbeta levels to inciease iesulting in faulty
scaffoluing
S. Skeletal: thin elongateu fingeis, limbs, hypeimobile joints, scoliosis, pectus
excavatum
4. Beait: uilation of ascenuing aoitic ioot, mitial oi aoitic ieguigitation
S. Eye: uislocateu lens
Y*<V/*&7' =%'"*'": !93 !*#2+%8'%G8'%'
1. AR lysosomal stoiage uisoiuei common in the Ashkenazi }ewish population
2. Fiameshift mutation in BEX A alpha subunit
a. Auuition of YFY6 in the BEX A gene foi the alpha subunit (8u% of A}
pop)
S. Accumulation of sphingolipiu uN2 gangliosiues
4. Newboins will appeai noimal until S-6 months of age until iapiu
mentalmotoi ueteiioiation, skeletal, &7"11< 1"G 9*&H+*, caiuiac,
iespiiatoiy uysfunction followeu by uementia, uifficulty swallowing,
paialysis, blinuness anu ueath by *2"' 3VE
/*#G78>> =%'"*'"
1. Nutation of the BexB gene anu piouuction of a G">"&$%-" @"$* 'H@H#%$ leaus
to the inactivation of both hexosaminiuase A anu B activity
2. Both hexosaminiuase A anu B activity iequiie a functional beta subunit.
S. The clinical couise of this uisease is similai to Tay-Sachs but with an
acceleiateu couise because of the *&&H9H+*$%8# 8> @8$7 !Z3 *#G
2+8@8'%G" in the lysosomes
/*#G78>> F&$%-*$81 =%'"*'"
1. Noimally hexosaminiuase A enzyme neeus an activatoi piotein calleu
Sanuhoff activatoi piotein gene, uefective oi absence of Sanuhoff activatoi
piotein leaus to uecieaseu hexosaminiuase A activity#8 ">>"&$ 8#
7"W8'*9%#%G*'" T *&$%-%$<
2. uN2 gangiosiue accumulates in the lysosomes anu the uisease symptoms anu
signs aie similai to Tay-Sachs uisease









Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
9


671898'89" 5N:
F+07* Y7*+*''"9%*:
1. Alpha globin is founu in both
*B FGH+$': cd\cd
@B )"$H'"': ce\ce
c. F#G %' $7"1">81" 01"'"#$"G *$ @%1$7ff
!" #$%&'( *+ ,$'$(-*.%
a. Z%'*+%2#9"#$M homologous paiiing anu iecombination between the
u1 anu u2 genes on sepaiate chiomosomes
S. Alpha-2: one loci is ueleteu!silent
4. Alpha-1 $1*%$: two loci aie ueleteu!milu miciocytic anemia
S. Bbh: thiee loci aie ueleteu, moueiately seveie anemia anu splenomegaly
a. Bouy tiies to use 4 beta subunits to compensate
NB T*1$'\;<G180' )"$*+%': ee\ee
a. uamma tetiamei iesults fiom compensation
b. Ineffective oxygen tianspoit, common in southeast Asians
c. Beath occuis in uteio oi shoitly aftei biith with massive geneializeu
euema
671898'89" 5O:
6*90$89"+%& =<'0+*'%*:
1. AB mutation of S0X9 gene on 17q
a. =H0+%&*$%8# 8> /UgS: gg 9*+"
b. ZH$*$%8# %# /UgS: gh >"9*+"
2. S0X9 usually initiates testis foimation even in the absence of SRY
S. 7S% of XY patients with this aie sex ieveiseu anu phenotypic females
4. Results in lethal skeletal malfoimations
67*1&8$ Z*1%" Y88$7
1. =H0+%&*$%8# of PNP22 on shoit aim
2. Bue to incieaseu piouuction of myelin, theie is an inability to maintain
compact myelin
S. Bistal leg muscle wasting, uemyelinating neuiopathy, piogiessive weakness
i%V)1*H9"#% /<#G189"
1. AB tiansciiption factoi uefect cieating a mutant TPSS gene foi pSS which is
usually a tumoi suppiessoi
2. Affecteu membeis in 7u% of families with LFS caiiy a mutant foim of TPSS
as a geimline mutation.
S. Nutations in both alleles aie necessaiy to inactivate the pSS gene
4. Raie cancei families with a histoiy of uiffeient foims of cancei (affecteu at a
ielatively eaily age) incluuing bone anu soft tissue saicomas, bieast cancei,
biain tumois, leukemia, anu auienocoitical caicinoma
S. _'H*++< 0LA '"#'"' &"++ '$1"'' 'H&7 *' =?F G*9*2" *#G &*H'"' *11"'$ %#
!5
*B Negatively iegulateu by binuing of NBN2
@B PSS usually binus p21 tiansciiption factoi.
?"H18>%@189*$8'%':
1. AB, loss of function mutation of NF1 causing cell piolifeiation
2. NF1 noimall acts as a $H981 'H001"''81 that activates RAS uTPase to
iegulate cell piolifeiation
S. Caf au lait spots hypeipigmentation, benign anu malignant tumois of the
neivous system, lisch nouules (iiis), pleiotiopic!!
/9%$7VZ*2"#$%':
1. Beletion of RAI1 gene on 17p
2. Nultiple congenital abnoimalities
S. Neivous system uevelopment flaws
4. Belayeu speech anu language
S. Bistinct facies, sleep pioblems, Behavioial Pioblems
671898'89" 5R:
Y1%'89< 5R:QG.*1GK' /<#G189"
1. Seveie malfoimation of the heait
2. Failuie to thiive, low postnatal suivival
S. Rockei-bottom feet, laige occiput, clenchingoveilapping pattein of fingeis
4. Pienatal Testing: uecieaseu PAPPA, Becieaseu hBCu, uecieaseu 0Se
concentiation, uecieaseu inhibin A
671898'89" 5S:
Z<8$8#%& =<'$1807< 5:
1. AB, Nutation of BNPK gene on chiomosome 19
2. 6_! iepeat in the -. /01 !2 )13498'$ 0+"%8$180%& 07"#8$<0" 8> *++ $7"
H#'$*@+" 1"0"*$ "W0*#'%8# G%'81G"1'
S. RNA binuing pioteins binu to the C0u iepeats when they shoulu be splicing,
causing uniegulateu splicing of theii noimal taigets!jaH"#&7%#2j
4. Bistal weaknesswasting, facial weakness, cataiacts, anu ptosis
S. Bypogonauism anu baluing
6. Babies have uifficulty swallowing, mentally ietaiueu
7. Insulin iesistance
Z<8$8#%& =<'$1807< 3:
1. Expansion of CCTu tetianucleotiue in the fiist intion of the gene enuocing
zinc fingei piotein 9
2. Iuentical phenotype of NB-1
671898'89" 34:
FG"#8'%#" ="*9%#*'" =">%&%"#&<:
1. AR iecessive mutation foi IL7 ieceptoi alpha chain as well as RAu1 anu
RAu2
2. BNA uegiauation can't occui
a. Accumulation of ueoxyauenosine occuis in B anu T lymphocytes anu
is toxic killing the cells by impaiiing BNA ieplication anu cell uivision
S. 6*H'"' /6D=: uevastating fungal, bacteiial, viial infections, infants will uie
fiom these without inteivention

Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
11

671898'89" 35:
Y1%'89< 35: =8.#K' /<#G189"
1. Beep simian gioove, white biush-fielu spot in iiis of eye, sanual gap toes,
small hanus anu feet, susceptibility to leukemia, susceptibility to Alzheimei's
because of 8-"1"W01"''%8# 8> Y*H.
2. Single most-common genetic cause foi moueiate mental ietaiuation
S. Nuch highei inciuence iate foi a chilu with uown's synuiome if the mothei is
ovei SS
4. 9S% of patients: mateinal non-uisjunction
S. 4% have 46 chiomosomes but have the uisease because of ,8@"1$'8#%*#
Y1*#'+8&*$%8#
a. Between 21q anu the long aim of anothei *&18&"#$1%& &71898'89"
(14 oi 22), tianslocation chiomosome ieplaces one of the noimal
aciocentiic chiomosomes
b. N0 RELATI0N T0 NATERNAL AuE
6. Testing: incieaseu hBCu, uecieaseu 0eS, incieaseu inhibin A, uecieaseu AFP
concentiation, inciease in NT in the ceivical spine!euema (seen on
ultiasounu)
671898'89" 33:
33a55B3 ="+"$%8# /<#G189":
vaiiation in the symptoms of the uisease is ielateu to the amount of genetic mateiial
lost in auuition to Beueoige Synuiome
C- caiuiac, espcecially tetialogy of fallot
A- abnoimal facies
T-thymic aplasia
C- cleft palate
B- hypocalcemia
22
="!"812" /<#G189":
1. ="+"$%8#
2. Stiuctuial oi Functional uefects of the thymus
S. T-cell immunoueficiency
4. Bypopaiathyioiuism leauing to hypocalcemia
S. Conutiuncal heait uefects
k6)/: k"+8&*1G%8>*&%*+ /<#G189"
1. Palate abnoimalities such as cleft palate, high aicheu palate, bifiu uvula
2. Caiuiac uiseases, anu chaiacteiistic facial appeaiance
6*$VQ<" /<#G189":
5B =H0+%&*$%8#: Y"$1*'89< >81 33a
2. Buplicateu iegion is in an %#-"1$"G 81%"#$*$%8#f
S. 0culai coloboma
4. Congenital Beait Befects
S. Cianiofacial anomalies
6. Noueiate Nental Retaiuation

g 671898'89":
llgV+%#X"G 1"&"''%-": G*H27$"1' 8> *>>"&$"G 9*+"' .%++ @" 8@+%2*$" &*11%"1'
llgV+%#X"G G89%#*#$: G*H27$"1' 8> *>>"&$"G 9*+"' PDii ;FkQ $7" G%'"*'"

D#*&$%-*$%8#: epigenetic silencing via methylation of one of the 2X chiomosomes in
a female shoitly aftei feitilization
1. g%'$: gene that functions as an RNA (not tianslateu into piotein)
a. QW01"''"G 8# $7" %#*&$%-" g &71898'89"ll
b. Nacio B2A is the histone involveu with the Baii Bouy
2. Baii bouies= numbei of X chiomosomes - 1 (activateu X chiomosome)
S. Inactivation is what accounts foi the mosaicism seen in X-linkeu uominant
uisoiueis in females.
EB ?8#V1*#G89 %#*&$%-*$%8#:
a. Abnoimal X Chiomosome anu noimal
%B F@#819*+ g %' %#*&$%-*$"G
@B T*+*#&"G Y1*#'+8&*$%8#: pait of the autosome is on the X
chiomosome anu pait of the x is on the autosome
%B ?819*+ g %' %#*&$%-*$"G '8 $7"1" %' #8 +8'' 8> "W01"''%8# 8>
$7" 0*1$ 8> $7" $1*#'+8&*$"G *H$8'89"
&B _#@*+*#&"G Y1*#'+8&*$%8#: the uefective X has pait of an autosome
on it anu on top of that theie is alieauy two noimal copies of that
same autosome (C*1$%*+ $1%'89< >81 $7*$ '"&$%8#J
%B Y7" G">"&$%-" g %' %#*&$%-*$"G $8 01"-"#$ $7" $1%'89< 2"#"'
>189 @"%#2 "W01"''"G
u. D> $7" $1*#'+8&*$%8# %' @*+*#&"GM #819*+ g &71898'89" %' %#*&$%-"
e. _#@*+*#&"G 8>>'01%#2 8> * @*+*#&"G &*11%"1: only the tianslocation
piouuct caiiying the X-inactivateu chiomosome is piesent anu this
chiomosome is invaiiably inactivateu!noimal X is always active
6890+"$" F#G182"# D#'"#'%$%-%$< /<#G189":
1. X linkeu iecessive uisoiuei (gene is locateu on the autosomal iegion of the X
chiomosome!46XY caiiieis will always expiess this because they only have
one anuiogen ieceptoi gene on theii one X)
2. C*$%"#$ %' ENgh @H$ *00"*1' >"9*+"ff
S. Testiculai feminization, no menstiuation, infeitile
4. Beletion in anuiogen binuingBNA binuing uomains of the anuiogen
ieceptois, lack of anuiogen ieceptois on taiget cells
S. 46XY inuiviuual has female bouy contouis, absence of axillaiy haii, spaise
pubic haii, uevelopment of bieasts, infeitile, genuei assignment is not an
issue
68+81 T+%#G#"'':
1. X linkeu iecessive



Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
1S

T"&X"1' ZH'&H+*1 =<'$1807<
1. X-linkeu iecessive
2. Y1H#&*$"G G<'$1807%# I'781$"1J
S. 46% of ueletion mutations aie iepoiteu to be in the 'spectiin-like' iepeats
piesent between the NB2 anu C00B teimini, they aie m%#V>1*9"j
substantiateu by Westein blot anu histological immunofluoiescent staining,
using anti-uystiophin antibouies
4. CK level is only slightly elevateu at time of onset
S. IQ pioblems, less aggiessive than Buchenne's, onset is at 11 (if still walking
at age 16BNB uiagnosis) patients iemain ambulatoiy well into auult life,
slightly ieuuceu life expectancy
=H&7"##" ZH'&H+*1 =<'$1807<:
5B gV+%#X"G @H$ #8$ 1"&"''%-"ffff
2. Causeu N4n 8> $7" $%9" @< * G"+"$%8# in the uystiophin gene
a. Analyzeu by Nultiplex CBR
S. Nost female caiiieis will at least uevelop caiuiomyopathy
4. Fiameshift mutations, uuplications
S. Bystiophin noimally links laminin to actin cytoskeleton in the ECN between
muscle cells
6. Pseuuohypeitiophy of calves, uowei maneuvei, elevateu seium cieatine
kinase, piogiessive muscle weakness,
7. 0nset S-S anu ueath befoie teen yeais fiom caiuioiespiiatoiy failuie.
)1*2%+" g:
1. X-linkeu uominant mutation in the FNR1 gene, abunuance of Cuu iepeats in
the S' 0TR of the fiist exon (gieatei than 2uu iepeats iesults in
hypeimethylation of the piomotei)!!"#" /%+"#&%#2
a. 0ccuis almost exclusively uuiing gametogenesis in the female
b. Seveiity of phenotype uepenus on the numbei of iepeats
2. Penetiance in females is at Su-6u%
S. Nost likely fiom mom
4. Coaise facial featuies, macio-oichiuism, veiy low IQ, behavioial pioblems,
long face, piominent jaw, piotiuuing eais, high aicheu palate
S. Seconu most common foim of milu mental ietaiuation in boys
)1*2%+" g *''8&%*$"G $1"981\*$*W%* '<#G189" )gYF/
1. Late-onset, piogiessive ceiebellai ataxia anu intention tiemoi uue to the
foimation of intianucleai neuional inclusions. Eviuence suggests that FXTAS
iesults fiom the 2 to S folu incieaseu levels of the FNR1 mRNA piesent in
these patients, iepiesenting a 2*%#V8>V>H#&$%8# 9H$*$%8#B
2. FNRP: RNA binuing piotein that associates with polyiibosomes to suppiess
the tianslation of pioteins fiom its RNA taigets. These taigets aie involveu
in cytoskeletal stiuctuie, synaptic tiansmission anu neuional matuiation.
The uisiuption of these piocesses is likely to unueilie the mental ietaiuation
anu leaining abnoimalities seen in fiagile X patients.
S. FNRP appeais to iegulate the tianslation of pioteins iequiieu foi the
1"2H+*$%8# 8> '<#*0$%& 0+*'$%&%$<, a piocess ciitical to leaining anu memoiy.
!+H&8'"VNVC78'07*$" ="7<G182"#*'" =">%&%"#&<I!NC==J:
1. X-linkeu iecessive that affects 1u% of Afiican-Ameiican males
2. u6PB is ueficient anu usually is asymptomatic unless tiiggeieu by ceitain
G1H2' $7*$ %#&1"*'" ,U/ (ieactive oxygen species)
a. F#$%V9*+*1%*+M 'H+>8#*9%G"'M *#*+2"'%&'M #8#V'H+>* *#$%@%8$%&'
b. C1%98aH%#"
c. Favabeans!Favism
S. RBCs of these patients aie moie susceptible to oxiuative uamage anu
oveipiouuce NABPB which usually piotects the cell fiom oxiuative uamage
by iegeneiating ieuuceu glutathione in its oxiuizeu foim, hemoglobin will
piecipitate as ;"%#] @8G%"'M anu membiane lipius may unueigo
peioxiuation weakening the RBC membiane causing hemolysis
4. Symptoms incluue hemolytic anemia, fevei, jaunuice, ieuuish biown uiine,
acute ienal failuie
S. **Accumulation of R0S in RBCs gives a peison a piotection against
malaiia!heteiozygote auvantage.
;"9807%+%* F:
1. X linkeu iecessive
2. Lack of factoi 8
S. Excessive bleeuing because bloou cannot clot piopeily
^+%#">"+$"1K' /<#G189"
1. Buplication of X chiomosome
2. Tall, thin males with ielatively long legs, hypogonauism, gynecomastia,
infeitility, leaining pioblems, pooi psychosocial aujustment, naiiow
shoulueis anu chest, may go unuiagnoseu until teen yeais when the male
uevelops bieasts
,"$$ /<#G189":
1. X-linkeu uominant expiesseu exclusively in females +"$7*+ %# 7"9%]<28H'
9*+"' @">81" @%1$7 I#8 Z*+"V9*+" $1*#'9%''%8#)
2. Nutation in the X-linkeu NECP2 gene, a BNA-binuing nucleai piotein that
meuiates tiansciiptional silencing
S. Noimal pienatalneonatal giowth anu uevelopment followeu by iapiu onset
of neuiological symptoms anu loss of milestones fiom 6-18 months of age
4. Female patients become spastic, ataxic, autistic, 0H108'"+"'' .1%#2%#2 81
>+*00%#2 98-"9"#$' 8> $7" *19' *#G 7*#G', seizuies, theie will be a
peiiou of pseuuostabilization aftei which patients ueteiioiate to become
seveiely ietaiueu, spastic, iigiu, anu have scoliosis.
S. Patients may live into auulthoou but can uie of unexplaineu suuuen ueath.
YH1#"1K' /<#G189":
1. ="+"$%8#
2. 4SX genotype oi 46 Xi (Xq)
S. 2S% of patients aie mosaic, while 99% aie miscaiiieu
4. Webbeu neck, coaication of the aoita, shoit statuie anu infeitility piesenting
as amenoiihea uuiing pubeity

Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
1S

h 671898'89":
Psueuoautosomal iegion: segments on the X anu Y that paii anu unueigo
iecombination uuiing male meiosis, impoitant in noimal male uevelopment
=Fg 2"#": suppiesses activity of SRY
/,h 2"#": Sex-ueteimining-uene
1. N0T L0CATEB in the pseuuoautosomal iegion
2. Lost to the X chiomosome uuiing iecombination iesults in a 46XXmales
S. If the SRY gene is ueleteu, 46 XY females
F`)& 2"#": (pait of the family of AZF iegions on the Y chiomosome)
1. Contains speimatogenesis genes
2. Nutations can iesult in infeitility
ZH+$%>*&$81%*+ =%'81G"1':
F+]7"%9"1K' =%'"*'": anu the Secietases
1. PSEN1: Piesenillin, Chiomosome 14
a. Eaily 0nset Alzheimei's: SS-6u
b. 1u% of all Alzhemiei's patients
c. uain of Function mutation (1 anu 2) in gamma secietase cofactoi
2. 1-2% of patients, 4u-8S yeais of age onset
a. TFCC: Beta amyloiu piecuisoi piotein,Chiomosome 21--BS
b. C/Q?3: Piesenillin, Chiomosome 1
S. ApoE: 671898'89" 5S late onsetmost common
a. Complex inheiitance Alzheimei's
b. Susceptibility allele
c. Nany genes but e4 allele is most commonly associateu anu founu in
the plaque accumulations
u. E4E4 homozygotes have highest piobability of getting Alzheimei's
4. Extiacellulai Accumulations: ApoE anu B42
S. Intiacellulai Accumulations (intianeuional): hypeiphosphoiylateu Tau
a. Neuiofibiillaiy Tangles!Tau is #8$ 9H$*$"G %# F+]7"%9"1K'
6. F+07* /"&1"$*'": goou!Claves BAPP!AB4u fiagments!nontoxic
7. T"$* *#G !*99* /"&1"$*'"': Bau!AB4u anu AB42 fiagments
a. AB42 is fibiillinogenic
=%*@"$"' Y<0" D D==Z:
1. uenetic susceptibility anu subsequent enviionmental insult
2. Chiomosome 6: NBC Class II BLA-BRS anu BR4 susceptibility loci
a. 9S% of patients expiess a BRS oi BR4 allele oi both compaieu to Su%
of contiols
b. BQB1*u2u1 allele segiegates with BRS
c. BQB1*uSu2 allele segiegates with BR4
S. CTLA4, PTPN22, insulin genes can also be mutateu




Q7+"1K' =*#+8' /<#G189" IQ=/J:
1. Nutations aie on 1S of the 24 chiomosomes, 1u uiffeient inheiiteu
connective tissue uisoiueis!Clinically heteiogeneous
a. QuantitativeQualitative abnoimalities in collagen synthesis
b. Some aie AB some aie AR
c. i<'%#" 7<G18W<+*'" %' 9H$*$"G!no hyuioxylysine
2. Chaiacteiizeu by joint hypeimobility, cutaneous fiagility, cigaiette papei
skin, hypeiextensibility, sutuies fall out aftei suigeiy
DG%80*$7%& 6"1"@1*+ k"%# Y7189@8'%':
1. Enviionmental Factoi
a. 0ial contiaceptives inciease the expiession of:
i. Factoi X
ii. Piothiombin
2. uenetic Factoi
a. Factoi v (Lieuen)
b. Piothiombin
;"1"G%$*1< ?8#08+<08'%' 68+8# 6*#&"1 I;?C66J
1. Nutations in genes NLB1, NSB2, NSB6 BNA mismatch iepaii pioteins aie
mutateu NutL oi NutS
2. Pieuisposition iesulting in 2-S% of all coloiectal cancei cases, most common
autosomal uominant inheiiteu foim of coloiectal cancei8u% iisk of
ueveloping an eaily onset inteinal cancei.
S. Causeu by inheiiteu uefects in BNA NNR (mismatchiepaii) with S uiffeient
NNR genes linkeu to BNPCC!NLB1, NSB2, NSB6 being the most common
(piototypical caietakei TSus)
4. Seconuaiy mutations: othei TSus incluuing APC anu TuFBR2
S. RER+ (ieplication eiioi positive) phenotype seen in cells lacking both copies
of Z/;3 incluues enoimous inciease in point mutations anu instability of
BNA segments contain simple sequence iepeats!Niciosatellite
polymoiphisms
6. Polyps will be in the G8]"#' #8$ $78H'*#G'
;%1'&7'01H#2 =%'"*'"
5B Can be inheiiteu F=, F, anu multifactoiial
3B ,QY +%2*#G F= foim, long segment foim iesulting fiom a loss of function
*B ,QY %' *+'8 *# 8#&82"#"
AB !=?)M Q=?,TM Q=?A /781$ '"29"#$ >819M &890+"W\9H+$%>*&$81%*+
a. Z8'$ &8998# 0*$$"1#: thiee loci aie locateu at 54a, A0 *#G 5Sa
b. I = 1Suuu; males have a 2x highei iisk
c. Complete absence of some oi all of the intiinsic ganglion cells in the
colon iesulting in '"-"1" &8#'$%0*$%8#M '<90$89' 8> %#$"'$%#*+
8@'$1H&$%8#M *#G 9"2*&8+8#
u. Paiasympathetic neivous system is impaiieu, incapable of peiistalsis
e. k"1< 7%27 1"+*$%-" 1%'X 1*$%8 >81 '%@' Io344J, but NZ twins uo not
show peifect concoiuance


Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
17

)*9%+%*+ ;<0"1&78+"'$"18+"9%*:
1. Nutations aie: Small nucleotiue subs, uels, ins
a. 2-1u% of the time is stiuctuial ieaiiangement
2. LBL ieceptoi
a. Loss of function, Chiomosome 19
S. ApoB1uu Binuing uomain
a. Loss of function, Chiomosome 2
4. PCSK9 piotease
a. uain of function, Chiomosome 1
b. Some vaiiants can be beneficial anu lowei LBL levels
S. ARB
a. Loss of function, Chiomosome 1
;898&<'$"%#H1%*
1. FH$8'89*+ ,"&"''%-"
2. Inciease in substiate ueiivatives
S. Classic: uefective &<'$*$7%8#%#" @"$* '<#$7*'" Bomocysteine can't be
conveiteu to cystathionine, methionine anu homocysteine accumulate
4. Beficiency in its cofactoi vitamin B6 (pyiiuoxal phosphate)
S. Beficiency in methionine synthase oi its cofactois Folate anu vitamin B12
6. Clinical Piesentation: excessive bloou clotting in the aiteiies anu veins
$7189@8"9@8+%'9 %# -"%#'\*1$"1%"', acceleiateu atheiogenesis, similai to
Naifan's synuiome except that joints aie $%27$ (loose in Naifan's), ietinal
uamage, uamage to the neuional netwoik of the eye, anu even loss of vision,
lens uislocation (infeiomeuial uiiection (uown anu in), 9"#$*+ 1"$*1G*$%8#M
osteopoiosis, long-bone fiactuies,
7. Tieatment: special uiet iestiicteu in piotein anu methionine anu
sypplementeu with cysteine. 0ial pyiiuoxine piouuces a ueciease in plasma
methionine anu homocysteine concentiation in bouy fluius (Su% of all
patients expeiience ieuuction), Folate anu vitamin B12 (cobalamin) shoulu
be supplementeu. T"$*%#" can also lowei homocysteine levels.
U'$"82"#"'%' D90"1>"&$*:
5B 6Ui5F5 8# 671898'89" 5OM 6Ui5F3 8# 671898'89" O
a. 9u% of patients have mutations in both of these
i. 2 pio alpha1 chains, 1 pioalpha2 chain
b. Nissense Nutation in pio-alpha-1 chain: 1 noimal: S abnoimal chains
c. Nissense Nutation in Pio-alpha-2 chain: 1 noimal: 1 abnoimal chain
2. Type 1: #H++ 9H$*$%8#'!collagen maue is noimal but in ieuuceu amounts
a. AB, Nutations in mRNA stability
b. Niluest foim, @+H" '&+"1*, bones aie pieuisposeu to fiactuie,
tiiangulai face, biittle teeth, heaiing loss, spinal cuivatuie
AB Y<0" 3: Z%''"#'" 9H$*$%8#
a. New mutation, glycine is substituteu with a bulkiei anu moie positive
amino aciu in the caiboxy 2S of the chain! i"$7*+
b. Baby uies in uteio oi shoitly aftei biith

4. Type S: Z%''"#'" ZH$*$%8#
a. AB, piogiessive uefoiming, fiactuies aie piesent at biith,
uentinogenesis impeifect, heaiing loss, @+H" '&+"1*
LB Y<0" E: Z%''"#'" ZH$*$%8#
a. AB, #819*+ '&+"1*, 2
nu
miluest aftei type 1, spinal cuivatuie, shoit
statuie, heaiing loss, uentinogenesis impeifect
C8+<&<'$%& ^%G#"< =%'"*'"
1. AB, 8-1u% of all enu-stage ienal uisease patients
2. PKB1: Chiomosome 16, tiansmembiane ieceptoi-like piotein
a. 8S% of mutations
S. PKB2: Chiomosome 4, integial membiane piotein homologous to voltage-
activateu souium anu calcium channel
4. Pioteins aie locateu on the piimaiy cilia of each ienal tubulai cell
S. Nislocation of cell suiface pioteins that aie noimally iestiicteu eithei to the
basolateial oi epithelial suifaces of ueveloping ienal tubule cells
6. Fluiu flow usually tells the cell to stop piolifeiating anu to polaiize
a. Cells fail to sense fluiu flow!incieaseu piolifeiation iesulting in cysts
7. 2-hit mechanism of piogiessive ienal failuie, tumoi-suppiessois aie off anu
neoplasia occuis, bilateial lowei back pain, intiacianial sacculai aneuiysms,
mitial valve piolapse
,"$%#%$%' C%29"#$8'*:
1. Bigenic Inheiitance
2. Common cause of visual impaiiment uue to photoieceptoi uegeneiation
S. Can be AR, AB, X-linkeu oi complex
4. Nutations in 4S uiffeient loci
68#2"#%$*+ FG1"#*+ ;<0"10+*'%*V )"9*+" C'"HG87"19*0718G%$%'9
1. F,M 46XX have noimal ovaiian tissue but with ambiguous oi male exteinal
genitalia Nost common uefect is a ueficiency of 21-hyuioxylase I=112,Suu
iesulting in an *@#819*++< 7%27 *#G182"# +"-"+' in both XX anu XY patients
2. Can affect both male anu female patients, males will have piecocious (eaily)
pubeity veiy eaily at about age S.
S. Results in viiilization of female infants, ovaiian uevelopment is noimal but
excess piouuction of anuiogens causes masculinization (enlaigeu clitoiis anu
labial fusion)
4. 0luei patients will unueigo masculinization uuiing pubeity, ueepening of the
voice anu appeaiance of facial haii, failuie to menstiuate
/"-"1" 689@%#"G D99H#8G">%&%"#&< =%'"*'" /6D=
1. Autosomal: ABA anu PNP ueficiencies causing neuiouevelopmental uelay
inuicative of mental ietaiuation, uue to uiffeient causes than X-linkeu SCIB
2. X-linkeu SCIB "Bubble Boy"
*B mutations in the gamma chain of the subunit foi IL-2, IL-4, IL-7, IL-9
anu IL-1S cytokine ieceptois.
S. Chilu lacks almost all immune uefenses anu uevelops life-thieatening
infections causeu by bacteiia typical of a B cell ueficiency anu also by viiuses,
oppoitunistic geims in the case of a T cell ueficiency. Theie will be #8
$7<9H' 8# gV1*<.Najoi tieatment is neeueu to suivive beyonu infancy
Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
19

Z%$8&78#G1%*+ =%'"*'"': FiPFh/ ZFYQ,?Fi
i"@"1K' 7"1"G%$*1< 80$%& #"H180*$7<
1. Expiesseu phenotypically as the iapiu, painless bilateial vision loss uue to
optic neive atiophy in young auults
2. ZH$*$%8#' %# $7" 8W%G*$%-" 078'0781<+*$%8# %# &890+"W 5
S. Bepenuing on the mutation, theie is often some iecoveiy of vision but the
pathogenic mechanisms of the optic neive aie uncleai.
4. Affecteu inuiviuuals may be male oi female but penetiance is much highei in
males, about L4n 8> 9*+" &*11%"1' @H$ 8#+< *@8H$ 54n 8> >"9*+" &*11%"1'
G"-"+80 $7" '<90$89' IL:5 1*$%8J
S. The vaiiance in penetiance anu male bias of the phenotype have been shown
to be ueteimineu by a haplotype on the shoit aim of X chiomosome
a. Alcohol anu tobacco use incieases piobability of blinuness in caiiieis
anu act as optic neive toxins.
ZQiF/:
1. Point mutation in tRNA foi i"H&%#" S24S A!u
2. ;"$"180+*'9%&: vaiiable expiessitivity uue to piopoition of mutant to
noimal mitochonuiial BNA in cells
S. Symptoms appeai in chiluhoou following a peiiou of noimal uevelopment
with muscle weakness anu pain, loss of appetite, vomiting, seizuies,
iecuiient heauaches this piogiesses to stioke like episoues begging befoie
age 4u, which can piogiessively uamage the biain leauing to vision loss,
pioblems with movement anu uementia
4. Lactic aciu can builuup leauing to vomiting, abuominal pain, fatigue, muscle
weakness anu uifficulty bieathing, myoclonus, ataxia, heaiing loss, heait anu
kiuney pioblems, uiabetes anu hoimonal imbalances
ZQ,,):
2. mtBNA gene encouing the tRNA Lys is the gene most commonly associateu.
A!u tiansition at nucleotiue 8S44. Nutations aie usually piesent in all
tissues anu uetecteu via bloou leukocyte mtBNA.
S. Foui main symptoms aie : myoclonus, geneializeu epilepsy, ataxia anu
iaggeu ieu fibeis in the muscle biopsy.
4. Nultisystem uisoiuei chaiacteiizeu by myoclonus, epilepsy, ataxia, weakness
anu uementia. 0nset is usually in chiluhoou, occuiiing aftei noimal eaily
uevelopment. Piesents with heaiing loss, shoit statuie, optic atiophy anu
caiuiomyopathy, occasionally pigmentaiy ietinopathy anu lipomatosis aie
obseiveu.

Y1%'89%"':
These chiomosomes have the least numbei of genes, which is why they uon't iesult
in a spontaneous aboition. Chiomosome 21 has the smallest numbei of genes,
besiues the Y chiomosome, anu thus you see the most successful uevelopment in
this tiisomy.

?8#V=%'[H#&$%8#!F#"H0+8%G<:
Z"%8'%' D ?8#V=%'[H#&$%8#:
1. 0ogenesis** Enu piouuct is 1 gamete (egg) anu 2 polai bouies
a. 0vum iemains in Neiosis I uiplotene of piophase I fiom S months
of gestation until ovulation (pubeity anu beyonu)
i. Some eggs nevei leave this stage!-->ueath
b. This is why tiisomies happen!!!
c. Incieasing iisk with incieasing mateinal age
2. uene Implication: B0B1 foi inciease in nonuisjunction
S. S chiomosomes will be uiffeient

Z"%8'%' DD ?8#V=%'[H#&$%8#: 2 of the S chiomosomes will be iuentical
**Tuinei's Synuiome (X0) anu XXX in female meiosis, XXY Kleinfeltei's
1. Female uoes not complete Neiosis II until aftei feitilizationiemains in
metaphase II, ieleasing the final polai bouy

D#-*'%-" C1"#*$*+ =%*2#8'%':
6781%8#%& k%++H' /*90+%#2: 54V55 .""X' I5
'$
$1%9"'$"1J
1. CPN occuis in 2% of all samples
a. Theie can be a tiisomy confineu to the placenta
i. Fetus neeus to be checkeu foi $1%'89< iescue
2. 1% aboition iisk
F9#%8&"#$"'%' 5LV5N .""X' I3
#G
$1%9"'$"1J
1. Kaiyotyping anu BNA testing
2. Bone to measuie alpha fetopiotein (AFP) which can also be testeu foi with
mateinal bloou seium
a. NTB testing foi neuial tube uefects
S. 1% aboition iisk
?8#V%#-*'%-" C1"#*$*+ =%*2#8'%':
)%1'$ Y1%9"'$"1 p 55 *#G 5A .""X':
1. Pappa: uecieaseu in all tiisomies
2. hBCu: uecieaseu in 1S18 tiisomies, incieaseu in 21 tiisomy
/"&8#G Y1%9"'$"1 p 5L q 34 .""X':
1. NSAFP
a. Incieaseu concentiation if chilu has neuial tube uefect
i. **Folic Aciu pievents**
b. Becieaseu concentiation if chilu has 21 tiisomy
2. hBCu: uecieaseu in 1S18 tiisomies, incieaseu in 21 tiisomy
S. 0ES: uecieaseu in all tiisomies
4. Inhibin A: uecieaseu in 1S18 tiisomies, incieaseu in 21 tiisomy
S. _+$1*'8H#G:
a. Inciease in NT: inuicates euema in 21 tiisomy
b. Beteimines sex fiom week 1S on

Southern Blotting: DNA
Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
21

;<G*$%G%>819 Z8+"':
ll #819*+ >"$*+ G"-"+809"#$ 1"aH%1"' 9*$"1#*+ 2"#89" >81 >"$*+ G"-"+809"#$
*#G 0*$"1#*+ 2"#89" >81 "W$1*V"9@1<8#%& G"-"+809"#$
;<G*$%G 6<'$: abnoimal giowth of the choiionic villi causes the placenta to be
conveiteu into a mass of tissue iesembling a bunch of giapes with small, atiophic oi
no fetus piesent
6890+"$" Z8+"': Biploiu 46XX with all of the chiomosomes being /0($1.0' in
oiigin.
2SX speim!ovum with no nucleus!chiomosomes uouble
C*1$%*+ Z8+": Tiiploiu, 69 chiomosomes, extia set is pateinal in oiigin 2S of the
time, $.8 '0"19 *#G 8#" "22 IO4n 8> $7" $%9"J
U-*1%*# Y"1*$89*: benign tumoi that aiises fiom 46XX cells containing only
mateinal chiomosomes

Y7" 6"#$189"1" *#G ,"*11*#2"9"#$':
Centiomeie Position:
Z"$*&"#$1%&: shoit aim anu long aim aie faiily equal in size
/H@9"$*&"#$1%&: uneven aims
F&18&"#$1%&: veiy uneven aims with a stalk anu satellite compiising the
shoit aim: 1S, 14, 1S, 21, 22
Balanceu: ielatively common with no phenotypic effect, associateu iisk of abnoimal
offspiing
1. D#-"1'%8#': single chiomosome unueigoes two bieaks anu is ieconstituteu
with the segment in between the bieaks inveiteu
a. 0sually no abnoimal phenotype
b. Piogeny aie at iisk uue to the piouuction of abnoimal gametes uue to
the loop that is foimeu when the chiomosomes paii in Neiosis I
c. C*1*&"#$1%&: uoes not incluue the centiomeie, both bieaks occui in
one aim
i. _'H*++< T"#%2#M @H$ 2*9"$"' %# 8>>V'01%#2 7*-" *#
%#&1"*'"G 1%'X 8> &71898'89*+ *@#819*+%$%"'
u. C"1%&"#$1%&: incluues the centiomeie, has a bieak in each aim of the
chiomosome, making them easiei to iuentify
i. 0nbalanceu gametes with iecombinant chiomosomes having
@8$7 uuplication anu ueficiency of segments uistal to inveision
ii. Bighest chance of having abnoimal offspiing
%%%B Q%$7"1 7*-" 4 81 3 &"#$189"1"'
3B Y1*#'+8&*$%8#':
a. Recipiocal
b. Robeitsonian
0nbalanceu: Auuition oi missing chiomosomal mateiial; abnoimal phenotype



6*#&"1 Y1*#'+8&*$%8#':
1. Buikitt Lymphoma (non-Bougkin's)
*B Nyc (tiansciiption factoi) gene is unuei the influence of a stiong
enhancei fiom immunoglobulin heavy chain
@B Associateu with QTk, myc chiomosome 8!14
&B Soliu tumoi composeu of abeiiant B-cells
GB Common tumoi of chiluien in equatoiial Afiica
2. Philauelphia Chiomosome: CNL 9!22
*B Pioto-oncogene ABL on Chiomosome 9 anu BCR on Chiomosome 22
@B BCR-ABL piotein is hypeiactive, noimally functions as a cytoplasmic
tyiosine kinase
F11*< 6!;:
1. Result of 1.S:
a. Tiisomy foi the entiie chiomosome
b. Buplication foi pait of a chiomosome
2. Result of .S:
a. Nonosomy foi the entiie chiomosome
b. Beletion foi pait of a chiomosome
F#*+<]%#2 ,"0"*$':
1. Niciosatellites
a. PCR to test
b. Piimeis flank iegions of the miciosatellites
c. Co-uominant: inheiit one fiom each of youi paients
2. Ninisatellites
a. Southein Blot to test
b. Laigei iepeats
c. Restiiction enzymes at flank, iun out of gen, use BNA piobe foi
segment that was the minisatellite
!"#" Y7"1*0<:
1. vectois:
a. Retioviial uene Replacement: uiviuing cells only
b. Auenoviius uene Replacement: non-uiviuing cells only
i. Laigei BNA inseit auvantage
c. Aueno-associateu viius uene Replacement AAv:
i. Biviuing anu non-uiviuing cells
ii. No immune effects
2. Bone Naiiow Tiansplant:
a. Nucopolysacchaiiue uiseases
b. Kiabbe's uisease
c. ABA Beficiency!SCIB (autosomal)
S. Coiu Bloou Tiansplant:
a. Builei's Tieatment



Niiiam Beinstein
!"#"$%&' )%#*+ ,"-%". /01%#2 3453
2S

4. uentamicin Ataloien
a. Facilitatable skipping of a piematuie stop couon in mutant mRNA
b. Allows the full-length piotein to be maue (nonsense meuiateu)
c. Cystic fibiosis, Buchenne's Nusculai Bystiophy anu Beckei's
Nusculai Bystiophy tieatment
S. Cuicumin
a. Inhibits a calcium pump in the ER anu impaiis binuing of a uelta FSu8
mutant to chapeione
b. Allows noimal foluing of mutant piotein
c. Cystic Fibiosis patients
=1H2 Z"$*@8+%'9:
1. C7*'" 5 G1H2 9"$*@8+%'9 with cytochiome p4Sus that have veiy
polymoiphic genes, these mutations can altei the way a peison iesponus to
uiugs
2. P*1>*1%# *X* 68H9*G%#! pievents thiomboembolisms, vit-K antagonist
a. D#7%@%$' vitamin K epoxiue ieuuctase complex 1 (vK0RC1 gene)
which iecycles oxiuizeu vitamin K to its ieuuceu foim aftei it has
paiticipateu in the caiboxylation of seveial bloou coagulation pioteins
i. C18$7189@%# *#G )*&$81 kDD
b. 6hC36S "#]<9" that catalyzes the fiist step in waifaiin uegiauation
i. Allelic fiequency: 2u% in whites anu much lowei in othei
populations
ii. Beteios foi ueficiency: 2u% lowei uose of waifaiin to maintain
the same uegiee of ant-coagulation
c. k^U,65 "#]<9"
i. Baplotype A: sensitive
1. Piesent in SS% of whites, 89% of asians, anu 14% of
Afiican ameiicans
ii. Baplotype B
1. S-folu inciease in the mRNA level!inciease in the
amount of enzyme neeueu
u. Combineu:
i. Bomozygotes foi CYP2C9 ieuuceu activity alleles anu vK0RC1
A alleles iequiie 1S to 16 the waifaiin uose that a
homozygote noimal foi CYP2C9 alleles anu vK0RC1 B alleles
woulu neeu to achieve the same appiopiiate theiapeutic
iesponse









S. 68G"%#"!Z8107%#"
a. Conveision of coueine (weak naicotic uiug) to moiphine which is a
bioactive metabolite with a 1ux highei potency
b. Conveision is caiiieu out by CYP2B6
c. C881 9"$*@8+%]"1' caiiying +8'' 8> >H#&$%8# *++"+"' %# 6hC3=N >*%+
$8 conveit coueine to moiphine anu theieby ieceive little theiapeutic
benefit
i. These patients will expeiience pain uespite a laigei uose of
naicotic.
u. 0ltiafast metabolizeis can become iapiuly intoxicateu with low uoses
of coueine

C80H+*$%8# !"#"$%&'V;*1G< P"%#@"12: p
2
+ 2pq + q
2


Caiiiei Fiequency: 2pq
P + q = 1, if q is a small numbei (AR) then assume that p=1

=%'"*'" Y<0" D r s
AR q
2

AB 2q
X linkeu Recessive Q (males)
X linkeu uominant 2pq

Log scoies: inuicate genetic linkage: value gieatei than S,
Look foi Z-max: IB max-value, see theta value associateu with tha
!genetic uistance in cN, one cN uesciibes a iecombination fiequency of 1%