Disease Name

Hemophilia (classic)

Ornithine Transcarbamylase Deficiency

Fragile X
Glucose Phosphate Dehydrogenase Deficiency
(Favism)

Lesch Nyhan Syndrome

Diseases - X linked

Diseases - X linked

Duchenne Muscular Dystrophy

Androgen Insensitivity Syndrome

Rett Syndrome

Diseases - Mitochondrial

MELAS

Diseases - Mitochondrial

MERRF

Cystic Fibrosis

Sickle Cell Anemia

Diseases - Autosomal recessive with
heterozygote advantage

Beta-Thalassemia

Alpha-Thalassemia

Phenylketonuria

Diseases - Inborn errors of metabolism

Ornithine Transcarbamylase Deficiency

Tay Sachs Disease

Familial Hypercholesterolemia

Marfan Disease

Ehlers-Danlos

Diseases - Autosomal dominant

(negative)

Osteogenesis Imperfecta

Huntington's Disease

Achondroplasia

Familial Hypercholesterolemia

Limb-Girdle Muscular Dystrophy

Diseases - Examples of imprinting

Praeder Willi

Angelman Syndrome

Patau Syndrome

Edwards Syndrome

Down Syndrome

Diseases - Chromosomal

Diseases - Chromosomal

Turner Syndrome

Triple X Syndrome

Kleinfelter's Syndrome

XYY

DiGeorge Syndrome

Alzheimer's Disease
Diseases - Complex genetic

Autism

Gastroschisis

Treacher Collins Syndrome

Diaphragmatic Hernia

Pulmonary Hypoplasia

VACTERL

Esophageal Atresia

Tracheal-esophageal Fistula

Polydactyly

Holoprosencephaly

Exencephaly/anencephaly and Spina Bifida

ASD (Atrial Septal Defect)

Diseases - Errors in development

Diseases - Errors in development

VSD (Ventricular Septal Defect)

Persistent Atrioventricular Canal

Persistent Truncus Arteriosus

Transposition of the Great Vessels

Tetralogy of Fallot

Syndactyly

Synostosis

Hand Foot Genital Syndrome

DiGeorge Syndrome

Holt-Oram Syndrome

Fetal Alcohol Syndrome

Diseases - Fetal teratogenic

Retinoic Acid Embryopathy

Fetal Thalidomide Exposure

Xeroderma Pigmentosum

CML (Chronic Myelogenous Leukemia)

Neurofibromatosis

Breast Cancer

Diseases - Cancer related mutations

Diseases - Cancer related mutations

HNPCC (Hereditary Non-Polyposis Colorectal

Cancer)

FAP (Familial Adenomatous Polyposis)

Retinoblastoma

Li-Fraumeni

Disease Name
Wolf-Hirschhorn Syndrome
Cri du chat Syndrome
Miller-Dieker syndrome
WAGR syndrome
Williams syndrome

Ataxia-telangiectasia
Fanconi anemia
Bloom syndrome

Mode of Inheritance

Gene/Locus/Lo
cation

Nonspecific loss of function

X-linked recessive

F8 clotting
factor

Nonspecific loss of function

X-linked Recessive

OTCase

Trinucleotide Repeat Expansion

(CGG)

X-linked recessive

FMR1 (Fragile X
mental
retardation 1)

Nonspecific loss of function

X-linked recessive

G6PD

X-linked Recessive

HGPRT protein
(hypoxanthineguanine
phosphoribosyl
transferase)

Type of Mutation

Nonspecific loss of function

X-linked recessive

Dystrophin
gene

Nonspecific loss of function

X-linked recessive

Androgen
receptor

Nonspecific loss of function

X-linked dominant (not

compatible with male life
except in rare cases of
mosaicism and Kleinfelter's) MECP2

Point mutations in tRNA or rRNA

genes that inhibit mitochondrial
protein synthesis

Mitochondrial

Nonspecific loss of function

Varying genes

Point mutation, loss of function

Mitochondrial

tRNA Lys

Most common is F508, many

different etiologies

Autosomal recessive

CFTR

Autosomal recessive

HBB
(hemoglobin B)

Missense Mutation E6V

Mutation that reduces hemoglobin

production or stability; found in
Autosomal recessive; may
promoters, splice sites, and 3'/5'
be compound heterozygous
UTRs
with HBS
HBB

Mutation that reduces hemoglobin

production or stability;
Autosomal recessive

HBA

Nonspecific loss of function

Autosomal Recessive

PAH
(phenylalanine
hydroxylase)

Nonspecific loss of function

X-linked Recessive

OTCase

Autosomal Recessive

Hexosaminidas
eA

Autosomal dominant

Usually in LDLR
gene (LDL
receptor
protein)

Nonspecific loss of function

Nonspecific loss of function

Loss of function that does not

impede expression

Loss of function that does not

impede expression

Autosomal Dominant
Negative

Fibrillin protein
FBN1

Autosomal Dominant
Negative

Collagen
proteins
(COL;1/3/5;A1/
2

Loss of function that does not

impede expression

Various
proteins,
usually type 1
Collagen
Autosomal Dominant
protein COL1A1
Negative (except for 3 of the or COL1A2 or
collagen associated protein associated
mutations)
proteins

CAG trinucleotide repeat; affected

by anticipation
Autosomal Dominant

HTT gene

Gain of function mutation

FGFR3
(Fibroblast
Growth Factor
Receptor 3)

Autosomal Dominant

Nonspecific loss of function

Autosomal dominant

Usually in LDLR
gene (LDL
receptor
protein)

Activation of a cryptic splice donor Autosomal dominant or

site resulting in frame shift
recessive

Calpain 3 gene

Deletion of paternal PWS segment Maternally imprinted;

of chromosome 15 or maternal
Paternally
uniparental disomy
inherited/expressed

More than one

gene is
expressed in
this region;
chromosomal
abnormality

Deletion of maternal AS segment

of chromosome 15 or paternal
uniparental disomy

More than one

gene is
expressed in
this region;
chromosomal
abnormality

Paternally imprinted;
Maternally
inherited/expressed

Trisomy 18

Can be inherited via a

derivative chromosome
from a balanced
translocation, from germline
de novo imbalanced
translocation, from
robertsonian translocation,
or from germline
nondisjunction in either
meiosis 1 or 2
Trisomy 13
Can be inherited via a
derivative chromosome
from a balanced
translocation, from de novo
imbalanced translocation, or
from a germline
nondisjunction in either
meiosis 1 or 2
Trisomy 18

Trisomy 21

Can be inherited via a

derivative chromosome
from a balanced
translocation, from germline
de novo imbalanced
translocation, from
robertsonian translocation,
or from germline
nondisjunction in either
meiosis 1 or 2
Trisomy 21

Trisomy 13

XO genotype (sex chromosome

monosomy)

Arises from de novo

germline nondisjunction in
either meiosis 1 or 2

XO genotype
(sex
chromosome
monosomy)

XXX genotype (X trisomy)

Arises from de novo

germline nondisjunction in
either meiosis 1 or 2

XXX genotype
(X trisomy)

XXY genotype

Arises from de novo

germline maternal
nondisjunction in
meiosis1/2 or paternal
nondisjunction in meiosis 1 XXY genotype

XYY genotype

Arises only from paternal

nondisjunction in meiosis 2 XYY genotype

Chromosomal 22q deletion

Autosomal dominant; may

arise from a derivative
chromosome from a parent
with balanced translocation
or a de novo germline
deletion/translocation; also,
people with DiGeorge are
Chromosomal
reproductively fit and may 22q deletion
pass on their own deletions involving Tbx1

Not inherited in Mendelian

Complex genetic disorder with
fashion; may be familial
multiple loci and allele involvement multifactorial inheritance

Not inherited in Mendelian

Complex genetic disorder with
fashion; may be familial
multiple loci and allele involvement multifactorial inheritance
Not inherited in Mendelian
fashion; may be familial
multifactorial or arise from
Unknown; may be due to various de novo mutations in
mutations
germline

Unknown

Unknown

Unknown

Nonspecific loss of function

Unknown; may be due to various

mutations

Unknown; may be due to various

mutations

Seems to be mostly de novo TCOF1 gene

mutations, but the disease encoding the
does not cause infertility
treacle protein

Not inherited in Mendelian

fashion; may be familial
multifactorial or arise from
de novo mutations in
germline

Many cases
may be due to
insufficiency in
retinoic acid
signaling
pathways

Not inherited in Mendelian

fashion; may be familial
multifactorial or arise from
de novo mutations in
germline

Many cases
may be due to
insufficiency in
retinoic acid
signaling
pathways

Various mutations in the Shh

signaling pathway

Unknown

Suspected to
be Shh
signaling
pathway

Unknown; may be due to various

mutations

Not inherited in Mendelian

fashion; may be familial
multifactorial or arise from
de novo mutations in
germline

It is one of the
possible effects
of a disrupted
Shh signaling
pathway

Unknown; may be due to various

mutations

Not inherited in Mendelian

fashion; may be familial
multifactorial or arise from
de novo mutations in
germline

Suspected to be loss of function in

Shh regulatory protein
Unknown

Unknown; may be due to various

mutations

Not inherited in Mendelian

fashion; may be familial
multifactorial or arise from
de novo mutations in
germline

It is one of the
possible effects
of a disrupted
Shh signaling
pathway

Associated with
Gli3 mutations
affecting the
Shh signaling
pathway

Unknown, but
most likely due
to Shh signaling
pathway
(possibly Gli2)

Complex genetic disorder with

multiple alleles

Not inherited in Mendelian

fashion; may be familial
multifactorial inheritance

Unknown; it
may be related
to the Shh
pathway
(VACTERL)

Known causes include

chromosomal deletions and
genetic mutations that cause loss
of function

Tbx1 and Shh

signaling
pathway
Some causes are inherited in
components or
an autosomal dominant
regulators, also
manner
present in
retinoic acid
embryopathies

Same as ASD

Same as ASD

Same as ASD

Same as ASD

Same as ASD

Same as ASD, as far as I can tell

Same as ASD
Same as ASD,
as far as I can
tell (present in
VACTERL,
DiGeorge, and
Same as ASD, as far as I can Retinoic Acid
tell
Embryopathy)

Same as ASD, as far as I can tell

Same as ASD,
Same as ASD, as far as I can as far as I can
tell
tell

Trisomy 21, DiGeorge deletion,

mutations related to Shh

May be due to various kinds of

mutations, both loss of function
and gain of function

Varies

Trisomy 21,
Tbx1 deletion,
mutations
related to Shh

Autosomal recessive or
dominant

Associated with
gain of function
mutations in
FGFReceptors;
disruptions in
Hoxd13
patterning; and
mutations in
BMP
antagonists
(e.g. Noggin)

May be due to various kinds of

mutations, but the only ones
discussed in class are ones that
cause syndactyly and Hox11
signaling disruptions

Autosomal recessive or
dominant

As above in
syndactyly; also
Hoxd11

Loss of function or expression of

Hoxa13 or Hoxd13

Autosomal dominant

Hoxa13 or
Hoxd13

Chromosomal 22q deletion

Autosomal dominant; may

arise from a derivative
chromosome from a parent
with balanced translocation
or a de novo germline
deletion/translocation; also,
people with DiGeorge are
Chromosomal
reproductively fit and may 22q deletion
pass on their own deletions involving Tbx1

Nonspecific loss of function

Autosomal dominant

Tbx5

Not genetic; caused by etoh

consumption in pregnancy

Causes
downregulation
Not genetic; caused by etoh of Shh and
consumption in pregnancy retinoic acid

Not genetic; caused by excess

retinoid intake during pregnancy,
notably from acutane

Retinoids are
converted into
Not genetic; caused by
retinoic acid,
excess retinoid intake during mimicking
pregnancy, notably from
upregulation of
acutane
RALDH genes

Not genetic; caused by

Not genetic; caused by thalidomide thalidomide intake during
intake during pregnancy
pregnancy

Thalidomide
seems to alter
the regulation
of FGF proteins

Nonspecific loss of function

Autosomal recessive

XP genes

Chromosomal translocation that

creates a fusion protein Bcr-Abl,
gain of function mutation

T (9;22) fusion
Usually a de novo mutation of Bcr and Abl

Nonspecific loss of function

Autosomal recessive; as if
autosomal dominant due to
high rate of loss of
heterozygosity; highly
varying expressivity and
severity
NF1

Nonspecific loss of function

Autosomal recessive; as if
autosomal dominant with
45-60% penetrance

BRCA1/BRCA2

Nonspecific loss of function

Autosomal recessive; as if
autosomal dominant with a
varying penetrance; 90% in
males, 70% in females
Various Genes

Nonspecific loss of function

Autosomal recessive; as if
autosomal dominant due to
70% Loss of Heterozygosity APC

Nonspecific loss of function

Autosomal recessive; as if
autosomal dominant due to
incredibly high risk of LOH Rb gene

Nonspecific loss of function OR in

rare cases gain of function

Autosomal recessive OR
autosomal dominant

TP53 gene P53

protein

Mode of Inheritance

Gene/Locus/Lo
cation

Type of Mutation

4p16.3 deletion WHCR

5p15.2 deletion, CDCCR, CLCR
17p13.3 microdeletion, LIS1 gene, 14-3-3e gene
11p13 microdieletion
7q11.23 microdeletion

WT1 gene, PAX6 gene

WBSCR, ELN gene, LIMK1 gene

DNA recomb repair enzymes, 11q22 ATM gene

DNA recomb repair enzymes, 16q24, FA-A gene
DNA repair enzymes, 15q26, BLM gene

Function Altered

Coagulation of blood

Clinical Presentation
Delayed clotting/excessive bleeding; joint
swelling and pain; degenerative arthritis;
hematuria

Deficiency in OTCase
prevents proper function
of the urea cycle by
blocking the synthesis of
citrulline from carbamyl
phosphate and ornithine,
causing a buildup of urea
which is toxic to the brain

Hyperammonemia causing hepatic

encephalopathy causing tachypnea and
vomiting, which in turn cause respiratory
alkalosis and dehydration, respectively, and
then hypothermia; hepatic encephalopathy
also causes seizures, lethargy;
hepatomegaly; has rapid onset in neonate
several days after birth

Normal expression of
FMR1 is reduced due to
expansion of methylated
CGG repeats
Loss of G6PD function;
first step of pentose
phosphate shunt

Severe mental retardation; long face; large

ears; prominent jaw; macroorchidism
(congenital giant gonads)
Hemolytic anemia after consuming high
quantities of oxidative compounds, like
found in fava beans; neonatal jaundice

Loss of function of HGPRT

results in halting of the
purine salvage pathway,
resulting in conversion of
hypoxanthine to xanthine
and then uric acid by
xanthine oxidase

Mental retardation; repetitive motions;

involuntary facial grimacing; self mutilation
involving lip, finger, and fingernail biting as
well as head banging

Gradual degredation of motor and muscle

function that begins at the hips and
progresses superiorly to the shoulders and
distally to the hands and feet; muscle
atrophies and is replaced by fat or fibrous
Dystrophin is thought to tissue; boys are often wheelchair bound by
participate in a complex their teen years, and life expectancy is
that plays a role in linking about 25-30 upon gradual paralysis of the
the cytoskeletons of
neck, shoulders, heart and diaphragm; later
muscle fibers with the
symptoms inclute spine or other bone
extracellular matrix
deformities
Complete androgen insensitivity: no male or
female parts or internal sex organs; usually
identified at puberty due to lack of
menstruation, but breasts do develop
In intermediate insensitivity: may develop
ambiguous genitalia, neither completely
Loss of function of
male or female, sometimes called a
androgen receptor protein "hermaphrodite" but that may be perceived
results abnormal male
as a negative label
development; severity is In reduced insensitivity: may develop
based on how poor
external male genetalia, but with
receptor function is
hypospadius, cryptorchidism, or infertility

Loss of MECP2 function,

disrupting the DNA
methylation pathway

Inability to produce
mitochondrial proteins
results in inactivation of
the TCA cycle and/or
electron transport chain
causing a backup,
ultimately resulting in
lactic acidosis

Normal development until 6-18mo of age,

followed by neurodegeneration, loss of
acquired speech and skills, loss of motor
skills in hands; acquired microcephaly;
mental retardation; seizures
Mitochondrial Encephalopathy, Lactic
Acidosis and Seizure-like episodes;
symptoms appear after a period of normal
development; muscle weakness and pain;
recurrent headaches; loss of appetite and
vomiting; seizures; later in age, stroke-like
episodes without ischemic events that, if
recurrent, can damage the brain and lead to
vision loss, movement problems, and
dementia

Myoclonic Epilepsy with Ragged Red Fibers;

Progressive myoclonic (muscular) epilepsy;
Nonfunctioning tRNA Lys ragged red fibers - aggregations of diseased
results in the inability to mitochondria in subsarcolemmal region of
produce mitochondrial
muscle fibers; short stature; hearing loss;
proteins necessary for TCA lactic acidosis; exercise intolerance; poor
and Ox-Phos
night vision
Commonly, pancreatic insufficiency;
gastrointestinal/nutritional insufficiency;
Poor Cl transporter
high salt loss through sweat; chronic
activity; insufficient
bronchopulmonary infection; sometimes
transcription; poor
infertility; frequency varying by population trafficking of Cl trasporter; 1/29 in Ashkenazi Jews, 1/28 in N.
functional protein but
Americans of N. European descent, and
rapid degredation
1/61 in African Americans
Low oxygen states cause hypertension,
anemia, stroke, and ischemic pain; ischemia
Hypoxic state causes HBSS of the spleen requiring splenectomy is
to partially denature and common at a young age; septicemia risk in
form an aggregate
the first 3 years of life

Loss of HBB chains results

in poor functioning or
nonfunctioning globin
tetramers; if it is
compound heterozygous
with sickle cell HBB (HBS),
the patient presents as
sickle cell homozygous

Compound heterozygotes as sickle cell

anemia homozygotes but not as severe;
beta-thalassemia homozygotes have
transfusion dependent anemia with facial,
skull, and other bone abnormalities due to
expansion of the bone marrow

Loss of HBA chain results

in HBB tetramers which
are unstable and lead to
hemolysis; called HB H
disease

Hemolytic anemia, edema, and heart

conditions

Difficulty in executive function, social

difficulties, eczema, irritability,
psychological or behavioral issues, loss of
IQ; when untreated, mental retardation,
seizures, and tremors; PKU can be
completely controlled with diet alone, but it
Deficiency in PAH
is INCREDIBLY difficult - must completely cut
prevents conversion of
out all meat, eggs, legumes, dairy, and most
phenylalanine to tyrosine, grains, can mostly only eat fruits and
which at increased
vegetables with awful tasting protein
concentrations is toxic to supplements; a single day of poor eating can
the brain
result in a permanent loss of IQ

Deficiency in OTCase
prevents proper function
of the urea cycle by
blocking the synthesis of
citrulline from carbamyl
phosphate and ornithine,
causing a buildup of urea
which is toxic to the brain
A sphingolipidosis, a
subset of lysosomal
storage diseases that
prevents metabolism of
complex fatty acids; an
accumulation of
sphingolipids in cell
membranes and myelin
sheaths results in
neuronal distension
followed by CNS and
systemic defects
LDL receptor is important
in the uptake of
chylomicron, VLDL, and
IDL remnants, as well as
LDL lipoproteins (via ApoB
interaction); causes an
overall increase in bodily
cholesterol

Hyperammonemia causing hepatic

encephalopathy causing tachypnea and
vomiting, which in turn cause respiratory
alkalosis and dehydration, respectively, and
then hypothermia; hepatic encephalopathy
also causes seizures, lethargy;
hepatomegaly; has rapid onset in neonate
several days after birth

Mental retardation; blindness; cherry red

spot on retina; rapid disease progression of
mental and physical deterioration of other
senses, movements, and the ability to
swallow; in infantile Tay-Sachs, death
usually occurs before age 4

Hypertension due to occlusive arterial

disease and atherosclerosis; accelerated
heart disease and angina; heart attacks,
transient ischemic attacks, and strokes;
visible deposits of cholesterol on the skin in
yellow patches, particularly above the eyes;
milky blood

High variability of expression requires

complex diagnostic criteria (Ghent):
With contributing family history, one major
organ system involvement and minor
involvement of another system. (major in
brackets, minor not)
Without contributing family history, two
major organ system involvements and
minor involvement of a third system.
Skeletal: [4 pectus carinatum, severe
pectus excavatum, long limbs, scoliosis,
wrist and thumb signs, medial displacement
of medial malleoli causing pes planus (flat
feet) and protrusio acetabulae (hip socket is
too deep into the pelvis)]; 2 major or one
major and two of the following - moderate
pectus excavatum, joint hypermobility,
highly arched palate with teeth crowding,
abnormal facies
Ocular: [2 of the following minor conditions]
- flat cornea, increased axial length of the
Expression of bad fibrillin eye, decreased pupillary miosis (constriction
gene interferes with
response)
normal protein function, Cardiovascular: [dilation of the ascending
has widespread systemic aorta involving the sinuses of valsalva,
effects
dissection of ascending aorta]; mitral valve
Joint hypermobility, frequent dislocations or
joint subluxations; skin is hyperextensible,
soft, easy to tear and bruise; poor wound
healing; mitral and aortic valve problems;
premature arthritis; the most severe and
rarest vascular type has less joint
involvement but more smooth muscle
Expression of bad collagen issues including arterial dissections and
protein interferes with
intestinal rupture, abnormal facies with
normal collagen function, large protruding eyes and thin face,
can affect many parts of transluscent skin, and prone to collapsed
the body
lungs

Eight different types depending on the

mutations involved, all but one are any
combination of 1) generally lethal, 2)
deforming, or 3) mutations not in collagen
but in collagen associated protein; the one
that is none of these is type I osteogenesis
imperfecta, a mild, null COL1A1 mutant that
is autosomal dominant negative and due to
de novo mutation in the germ line ~60% of
Expression of bad collagen the time; symptoms include loose joints,
protein interferes with
spinal curvature, poor muscle tone, slight
normal collagen function, protrusion of the eyes with grey blue sclera,
can affect many parts of easily fractured bones, and possibly early
the body
hearing loss
Risk determined by number of repeats: <26,
normal; 27-35, risk for offspring; 36-39, at
CAG (polyglutamine)
risk, reduced penetrance; 40-55, adult
repeat causes some HTT onset; >55, juvenile onset(prior to age 20);
to misfold; misfolded
in rare cases, may occur in children;
proteins aggregate within symptoms include changes in memory and
neurons, preventing them behavior, particularly an increase in ager or
from being destroyed;
violence, depression, mania, and OCD;
aggregation leads to
inability to perform job duties; gradual loss
neuronal death and
of motor control, muscle movement,
plaque formation
speech, and cognitive ability; muscle spasms
Regularly, FGFs act to
initiate limb bud
outgrowth and then
perhaps have a negative
regulatory effect on bone
growth; studies show this
FGFR3 mutation is
constitutively active,
resulting in very short
bones

Improportionate dwarfism; shortening of

the proximal limbs, fingers and toes; large
prominent forehead with small midface and
flattened nasal bridge; spines and knees can
be bent one way or another (kyphosis or
lordosis and bowleg or knock knee)

LDL receptor is important

in the uptake of
chylomicron, VLDL, and
IDL remnants, as well as
LDL lipoproteins (via ApoB
interaction); causes an
overall increase in bodily
cholesterol

Hypertension due to occlusive arterial

disease and atherosclerosis; accelerated
heart disease and angina; heart attacks,
transient ischemic attacks, and strokes;
visible deposits of cholesterol on the skin in
yellow patches, particularly above the eyes;
milky blood

As muscular dystrophy

Like Duchenne Muscular Dystrophy, but

with varying expressivity and severity; it is
often not fatal, and sometimes distal motor
function is completely unaffected; however,
heart and respiratory function may still be
weakened; the most affected muscles are
those of the shoulder and hip girdles; age of
onset varies from 10-30 years; some
patients with mild forms live near normal
lives with little muscle weakness

Multigene syndromes
largely affecting the brain;
PWS genes and AS genes
are geographically very
close in the chromosome, Hypotonia, poor development, short
so it is common for both stature, small hands and feet, mental
to be deleted together
retardation, polyphagia, obesity is common

Multigene syndromes
largely affecting the brain;
PWS genes and AS genes
are geographically very
close in the chromosome, Extremely happy demeanor, waving of
so it is common for both hands and forearms with limp wrists and
to be deleted together
bent elbows like marionettes

Phenotypic findings are similar to those of

the embryonic signaling pathway
developmental disorders and include:
mental retardation, microcephaly,
holoprosencephaly, eye defects, and
meningomyelocele (mild spina bifida);
polydactyly, rocker-bottom feet, cleft
Extra copy of
palate, low set ears, missing skin or hair;
chromosome 13 causes
abnormal genitalia and kidney defects;
disease state due to gene heart defects
dosage effects
~80% of patients die by age 1

Microcephaly; low set, malformed ears;

Extra copy of
micrognathia and cleft lip and/or palate
chromosome 18 causes
(classical cleft or Pierre-Robin sequence);
disease state due to gene ocular hypertelorism with narrow palpebral
dosage effects
fissures and ptosis; cryptorchidism
Making a diagnosis: hypotonia; slanted
palpebral fissures, midface hypoplasia;
brushfield spots (white flecks in the iris); ear
anomolies and skin tags; high arched palate;
single palmar crease; wide spread large toe;
clinodactyly (inward bending of the fifth
finger)
Also, Down Syndrome patients often have
heart defects, obstructice bowel issues,
narrowing of developmental facial tubes
resulting in frequent ear and sinus
Extra copy of
infections, altered leukemia risks,
chromosome 21 causes
hypothyroidism, increases risk of seizures
disease state due to gene and Alzheimer's, pointed cornea, and
dosage effects
standing eversion of the feet

Often identified by phenotype at birth:

edema of the feet and hand, abnormal
facies, webbed neck, broad, shield shaped
chest, widely spread nipples
In development, they have short stature,
limited breast development, lack of
Monosomy of the
menstruation
pseudoautosomal regions Other symptoms include possible coarcation
of the X chromosome
of the aorta, infertility due to premature
results in
degeneration of ovaries, and kidney
haploinsufficiency
abnormalities

Trisomy of the
pseudoautosomal regions
of the X chromosome
causes only minor, usually
unnoticeable phenotypic
changes and few health
complications; often
undiagnosed
Two copies of X
chromosome in males
results in androgen
deficiency, affecting
develompent of
secondary sex traits;
typically not diagnosed
until puberty
Like XXX; very minor
phenotypical changes,
often going undiagnosed

Usually tall statured women with mild

developmental, learning, or speech
disabilities; no significant phenotypical
changes; usually fertile, but some may
become sterile; histology shows 2 Barr
bodies within cells

Tall with long legs; sexual immaturity and

hypogonadism; infertility; decreased muscle
tone; poor libido; decreased bone density;
gynecomastia with increased risk of breast
cancer; social dysfunction, poor verbal skills,
or social dysfunction
Tall stature; increased risk of behavioral
problems such as ADD/ADHD,
impulsiveness, and aggression; ~50% have
reduced IQ

Partial monosomy of the

22p11.2 section that
includes, most
importantly, the T-box1
(TBX1) gene results in
abnormal secondary heart
development and
development of
pharyngeal arch and
pouch structures, possibly
due to problems in neural
crest cell migration
Complex and poorly
understood genetic
interactions result in
plaques and tangles in the
brain, causing neurological
disorders; it is the most
common form of
dementia
Seems to be the cause of
a complex network of
genes responsible for
neural networking; MRI
shows nerve
fibers/pathways in
abnormal
patterns/regions of the
brain; may be a
positioning and signaling
issue
Unknown cause, but cell
migration and lateral
folding is disrupted,
resulting in failure to close
ventral wall

CATCH-22:
Cardiac abnormality (especially tetralogy of
Fallot)
Abnormal facies
Thymic aplasia (due to poor development of
pharyngeal pouch 3)
Cleft palate (due to poor development of
first pharyngeal arch)
Hypocalcemia secondary to
Hypoparathyroidism (due to poor
development of pharyngeal pouches 3 and
4)
Early symptoms are often mistaken as "age
related" concerns or manifestations of
stress, such as forgetting or misplacing
things; later symptoms include confusion,
irritability, aggression, mood swings, trouble
with language, and long term hearing loss;
bodily functions continue to deteriorate
Quick diagnosis: monotone voice, little
facial expression; social impairment; strict
adherence to routine; obsessions with facts
or collections, with superb memory; clumsy,
awkward
Other syndromic features: varying degrees
of mental retardation; seizures;
abnormalities of gait, posture, and balance;
sensory sensitivity/defensiveness; high pain
threshold

Viscera of the body, including the heart,

may be exposed

This mutation results in hypoplasia of the

mandible and facial bones resulting in
narrow face and no zygomatic processes;
Disruption of TCOF1
low, malformed external and middle ears;
causes massive apoptosis very small chin that may lead to high or cleft
of neural crest cells in the palate and teeth probems; sagging or
first branchial arch via an drooping lower eyelids due to lack of
unknown mechanism
underlying structures
Unknown mechanism, but
cell migration of
pleuroperitoneal folds
from the the body wall to Lung and heart development may be
form the diaphragm is
impaired due to herniation of abdominal
disrupted, resulting in a
viscera into the thoracic cavity; presence of
connected
diaphragmatic hernia and pulmonary
pericardioperitoneal
hyperplasia may be indicative of retinoic
cavity
acid insufficiency
Retinoic acid is not only
responsible for anteriorposterior patterning of
vertebrae and hindbrain,
but also the foregut; lack
of RA signaling is
suspected to prevent the
activation of appropriate
Hox genes that determine
where the lung buds will
form, resulting in
improper development of
lungs

Children with pulmonary hypoplasia have

small lungs, and may be missing lobes or
entire lungs; pulmonary hypoplasia is a
common cause of neonatal death and a
common finding in stillbirths; while it is
largely fatal, it is not incompatible with life

Shh has a widespread

effect on multiple bodily
systems:
Expression in the
notochord has an effect
on somite migration to
form vertebral structures
Shh plays a role in
separating the cloaca into
an anal canal and a
urogenital sinus (kind of
like the lungs and
esophagus at the other
end)
Shh is necessary for
secondary heart field cell
migration and separation
of the great vessels
Shh plays a role in
separation of lung buds
from the esophagus
It forms a gradient in AP
limb patterning

VACTERL is an acronym for associated

symptoms, diagnosis is made if 3 or more
(according to lecture, not notes) are
present:
Vertebral defects including spina bifida
occulta, tethered cord, and abnormalities in
vertebrae and ribs
Anorectal malformations from imperforate
anus to fistula of the urinary tract and
digestive system
Cardiovascular defects including ASD,
persistent truncus, and tetralogy of Fallot
Tracheal-Esophageal fistula or esophageal
atresia
Renal dysplasia
Limb malformations

Knockouts in Shh in mice

models show that Shh
plays a role in separating
the lung buds from the
esophagus; in esophageal
atresia, the proximal and
distal segments of the
esophagus are not
continuous, and the
proximal end may
terminate in a blind sac

Esophageal atresia with proximal blind sac

results in persistent regurgitation of food
after feeding; esophageal atresia may
occure with or without the distal esophagus
opening into the trachea; if it does, air can
be forced into the stomach through the
fistula while coughing; while a patient in this
case cannot feed, if for any reason they
have stomach contents this may result in
their regurgitation into the trachea

Knockouts in Shh in mice

models show that Shh
plays a role in separating
the lung buds from the
esophagus; in trachealesophageal fistula without
atresia, the esophagus is
continuous but has an
abnormal opening into the
trachea distal to the
epiglottis

Tracheal-esophageal fistula may cause air to

be forced into the stomach through the
fistula while coughing, which may result in
the regurgitation of food and other stomach
contents into the trachea

Gli3 restricts Shh signaling

to the zone of polarizing
activity and the ulnar or
caudal aspect of the limb
bud and developing arm,
from where it creates a
gradient for
anterior/posterior
patterning; in Gli3
mutants, Shh is allowed to
be expressed in other
cells, creating multiple
overlapping gradients and
extra fingers

Polydactyly is typically preaxial or postaxial,

but it can also be central; preaxial
polydactyly means to have an extra thumb,
postaxial means to have an extra fifth
finger, while central polydactyly means to
have a duplicate index, middle, or ring
finger, in order of prevalence

Midline brain and craniofacial defects that

usually result in the absence of normal
Unknown cause, but
structures and vary in severity from very
suspected to be disrupted mild brain malformations and normal facies
Shh signaling causing
to severe: cyclopea; absence of nasal
midline neural and
septum; single nostril; single incisor; cleft
craniofacial patterning to lip; single small cerebral hemisphere due to
be disrupted
incomplete division of the forebrain

Exencephaly/anencephaly results in a still

birth of a child without a brain - the brain
develops normally but is degraded by
exposure to the amniotic fluid; as a result of
not having the brain and skull to influence
migration of other derivatives, these
children also tend to have abnormally low,
compacted, and proportinately broad facial
features
Spina bifida most commonly occurs at the
lumbar spine and varies in severity - some
defects may be as severe as an open
vertebral canal which exposes the spine to
Exencephaly/anencephaly amniotic fluid and begins degredation;
and spina bifida are
others may have exposed dural sacs that
caused by incomplete
have herniated out of lesions, or they may
closure of the neural tube even be too small for that to occur (spina
during development at
bifida occulta); in severe cases, the children
the head and most
are paralyzed, in less severe cases they are
commonly the lumbar
normal with surgical repair, in the most mild
spine, respectively
there is no intervention necessary

The septum primum and septum secundum

are like two overlapping sheets of paper
with holes cut out of them, with the septum
primum on the left and the septum
secundum on the right; the septum
secundum is held in place while the septum
primum is allowed to flap away from it;
before birth, the right atrium is at higher
pressure which causes the septum primum
to flap, allowing blood to travel through
both holes to the other side
An atrial septal defect can be caused by
absence of either the septum primum or
septum secundum, or by excessive
apoptosis, each creating an open passage
Atrial septal defects can for the heart to flow through
arise from abnormalities An atrial septal defect is a local defect in
in Shh signaling (VACTERL) atrial septation that causes mixing of
causing improper
oxygenated and deoxygenated blood; after
migration to the heart to birth, the left side of the heart becomes
form septal structures
higher in pressure than the right, causing
blood to flow from left atrium to right
They may also arise from atrium
abnormalities in
secondary heart field cells A similar, but more severe defect in
(DiGeorge Tbx1 deletion) development is a common atrium where
that may result in poor
the entire atrial septum is missing; this is
migration, differentiation, caused by absolute absence of the septa
or survival (unknown
primum and secundum
mechanism)
A similar but less severe defect is a patent
foramen ovale, present in about 20% of
people: these are present when the septa
primum and secundum fail to fuse after
birth; they are generally asymptomatic
because the higher pressure on the left
after birth pushes the two together and, as
they have holes cut out at different spots,
prevent blood from flowing into the right
atrium

the entire atrial septum is missing; this is

caused by absolute absence of the septa
primum and secundum
A similar but less severe defect is a patent
foramen ovale, present in about 20% of
Retinoic acid
embryopathy also causes people: these are present when the septa
ASD as retinoic acid plays primum and secundum fail to fuse after
birth; they are generally asymptomatic
a role in neural crest
because the higher pressure on the left
migration to the AV
after birth pushes the two together and, as
cushions that form the
they have holes cut out at different spots,
bottom of the atrial
prevent blood from flowing into the right
septum- these neural
crest cells apoptose and atrium
do not contribute to
septal structures, but it is
suspected they play some
role in directing septation
In VSD, it seems that the
same defects that cause
malformation of atrial
septal structures also
prevents formation of the
ventricular septum; this is
most commonly due to
poor migration of
secondary heart field cells
to the outflow tract of the
primary heart tube; these
cells are major
contributors to the conal
cushions, which grow
down the heart to meet
the muscular ventricular
septum and the
endocardial cushions to
form the thin,
membranous portion of
the interventricular
septum (pars
VSD causes shunting of oxygenated blood
membranaceae)
from the left ventricle to the right ventricle

Persistent atrioventricular
canal is a similar but more
severe septal defect that
is esentially both an ASD
and a VSD, caused by the
failure of fusion between
the dorsal and ventral
endocardial cushions
during development; it
seems to be the result of
the same teratogenic
mutations and exposures
that cause ASD and VSD
Failure of cushion
development, defective
cushions, or abnormalities
in neural crest migration Outflow tract is not separated into
are possible causes for
pulmonary artery and aorta; lack of growth
persistent truncus
of conal cushions creates VSD
In development of the
outflow tracts, the conal
and truncal cushions
expand as septa to meet
in the outflow tract in a
spiraling fashion;
transposition is thought to
be caused by failure of
truncal cushions and septa
to spiral

Pulmonary artery and aorta swap outflow

tracts, with the aorta connected to the right
ventricle and the pulmonary artery
connected to the left

Tetralogy of Fallot consists of 4

malformations:
1) Overriding aorta
Cause of tetralogy of
2) Ventricular septal defect
Fallot in Down syndrome 3) Pulmonary stenosis
patients was never
4) Right ventricle hypertrophy, which I
discussed, but the cardiac believe is secondary to narrowed pulmonary
disruption speaker
artery and resultant pulmonary
mentioned their
hypertension
association; causes for
other mutations are
In tetralogy of Fallot, the conal septum is
similar to those for ASD
deviated, creating all four characteristic
and VSD
malformations
Mutations' effects on the
BMP pathway in limbs are
difficult to understand
because it not only results
in patterning apoptosis of
the digits but also the
condensation of cartilage
into bone; constitutively
active FGFRs signal cells to
resist patterning
apoptosis, preventing
separation of the digits;
mutations in BMP
antagonists may cause
syndactyly via improper
apoptosis or excessive
bone growth from
cartilage blueprints;
Hoxd13 mutations are
independent from BMP
pathways and result in
syndactyly due to
Any number of digits may be fused with
disrupted proximal-distal varying severity; in extreme cases, all five
patterning;
digits may be fused together

Synostosis is the fusion of

bones, with syndactyly
being a specific case; the
other case is caused by
disruption of Hoxd11
expression that results in
fusion more proximal to
disruption of Hoxd13
(numbers get smaller as
we approach the head);
mutations in FGFRs that
cause syndactyly may also
result in craniosynostosis
(premature fusion of the
skull)
Hox13 is expressed
caudally and distally on
appendages; loss of
appropriate expression or
function results in
improper development of
these regions
Partial monosomy of the
22p11.2 section that
includes, most
importantly, the T-box1
(TBX1) gene results in
abnormal secondary heart
development due to lack
of Tbx1 expression by
secondary heart field cells
and development of
pharyngeal arch and
pouch structures, possibly
due to problems in neural
crest cell migration

Abnormal absence of Hox11 in the presence

of Hox9 and Hox10 drives humeral fate in
forearm, causing fusion of the radius and
ulna; craniosynostosis phenotype depends
on which sutures fuse, but are always
indicated by abnormal cranial proportions for example, if the sagittal suture fuses
early, the brain will continue ot expand
posteriorly, resulting in an enlarged
occipitus and long, boat shaped head
Hand-foot-genital syndrome includes
extremely rare defects including
hypospadius (closure of urethra that leaves
opening on ventral aspect of penis); uterine
fusion defects; brachydactyly and
syndactyly or synostosis

CATCH-22:
Cardiac abnormality (especially tetralogy of
Fallot due to poor migration of secondary
heart field cells)
Abnormal facies
Thymic aplasia (due to poor development of
pharyngeal pouch 3)
Cleft palate (due to poor development of
first pharyngeal arch)
Hypocalcemia secondary to
Hypoparathyroidism (due to poor
development of pharyngeal pouches 3 and
4)

T-box 5 is required for

precardiac mesoderm
differentiation and early
cardiac development;
Tbx5 is also important in
forelimb development;
mutations in Tbx5 result in
malformations ("hearthand syndrome")

Mutations in Tbx5 may result in partial or

complete absence of bones of the arm, or
their underdevelopment; it also causes
carpal abnormalities and may cause
polydactyly or first finger hypoplasia
The most common heart defect is an ASD,
but may also present with VSD or cardiac
conduction defects

Downregulation of sonic
hedgehog and retinoic
acid causes death of
neural crest cells

Symptoms include brain, heart, facial,

palate, and finger problems: mental
retardation and microcephaly; cardiac
septal defects; narrow forhead and facial
hypoplasia; short, possibly slanted
epicanthal folds with palpebral fissures; thin
upper lip and hypoplastic philtrum; cleft lip
and palate; clinodactyly of pinky finger
Also, it apparently commonly affects
midline structures (even though the only
one left is the philtrum)

Increasing embryonic
retinoic acid may cause
problems in any
patterning retinoic acid
takes part in: posterior
and hindbrain fates;
proximal-distal limb
identity; regulation of
heart looping and
inflow/outflow
specifications; and neural
crest migration for
craniofacial development

Anterior/posterior and brain fates:

microcephaly, neural tube defects, mental
retardation
Limb defects
Septal heart defects: ventricular septal
defects, atrial septal defects, conotruncal
defects
Facial defects: narrow forehead, flat nasal
bridge, midfacial underdevelopment,
micrognathia, palate defects,
microphthalmia, microtia

Downregulation of FGF10
and FGF8 proteins causes
death of cells in limb bud
mesenchyme and the
apical ectodermal ridge;
thalidomide also acts as
an antiangiogenic factor,
preventing blood cells
prom perfusing the
developing limbs
Loss of function of XP
results in reduced
efficiency of nucleotide
excision DNA repair
mechanism in response to
UV light induced
pyrimidine dimers
Fusion of the two proteins
creates a constitutively
active tyrosine kinase that
activates many proteins in
the cell

Loss of neurofibromin
protein results in
unchecked neuronal cell
growth

dsDNA breaks are

repaired less efficiently

Thalidomide poisoning in the embryo

results most notably in truncation of the
limbs; additional deformities include those
of the eyes, hearts, gut, and urogenital
tracts

Sensitivity to sunlight, unusually high

number of freckles, irregular dark spots on
the skin, sensitive eyes
Leukemias are sometimes asymptomatic
and have rapid onset; often, they will
present as colds: malaise, body/joint pain,
low grade fever; other symptoms include
enlarged spleen, anemia, and easy bruising
Cafe au lait spots; proliferation of usually
small, benign tumors along the PNS,
although these may get quite large in some
patients; often the patients body will be
covered in little nodules where the tumors
are within the skin; some types include
hearing loss
Dramatically increased risk for breast cancer
bilaterally and at an earlier age of onset;
increased risk for ovarian cancer; increased
risk of prostate cancer for males with the
BRCA2 mutation

Mutation in proteins
involved in methyl
directed mismatch repair;
results in extremely high
DNA replication mutation
rate in microsatellites and
other simple repeat
sequences like those in
TGFBR2 and APC due to
polymerase slippage
APC no longer causes Bcatenin degredation,
which then builds up
freely in the cell and
induces
MYC(protooncogene)
expression

Abundant proliferation of benign polyps

within the colon, stomach, rectum, and
some in small intestine; usually has no
symptoms until the polyps have progressed
to a cancerous state; stomach polyps turn
cancerous much more rarely; disease may
accelerate with pregnancy

Similar to HNPCC, asymptomatic unless

seen with an endoscope; dense carpeting of
polyps all along the colon, usually starting
with the sigmoid and spreading proximally

Rb no longer inhibits E2F,

which then acts as a
transcription factor that
activates genes which
Germline mutation results in an incredibly
induce progression
high risk for bilateral retinoblastoma tumors
through cell cycle
of the eyes, requiring removal of the eyes
A high frequency of nonspecific cancer
types within the body or in a family; one of
the few cases where multiple types of solid
organ or tissue cancers ( such as
osteosarcomas) proliferate in unusual parts
Loss of "guardian of the
of the body; the most common kinds are
genome;" Cells with
breast cancers, brain tumors, acute
damaged genomes no
leukemias, soft tissue sarcomas,
longer arrest their cell
osteosarcomas, and adrenal cortical
cycles or apoptose
carcinomas

Function Altered

ene, PAX6 gene

R, ELN gene, LIMK1 gene

Clinical Presentation

Prominent forehead broad nasal root, short philtrum, down-turned mouth, congenital heart de
Round faces, catlike cry, congenital heart defects, microcephaly, mental retardation
Lissencephaly, microcephaly, high furrowed forehead, death early.
Wilms tumor, anridia, genitourinary abnormalities, (mental) retardation. Wilms most common
facial dysmorphology (prominent lips, wide mouth, short palpebral tissues, short upturned nos

ecomb repair enzymes, 11q22 ATM gene ionizing radiation sensitivity, cerebellar ataxia depletion of Purkinje, prog nystagmus, slurred sp
ecomb repair enzymes, 16q24, FA-A gene crosslinking agent sensitivity, caf-au-lait spots, hypogonadism, microcephaly, hypoplastic or ap
epair enzymes, 15q26, BLM gene
hypersensitivity to damaging agents, long narrow face, erythema with telangiectasia in butterfl

Treatments discussed in class

Citrulline supplementation, protein

restriction, arginine supplementation,
benzoic acid, and phenylacetate; liver
transplant

Avoid exposure to broad beans and

other foods high in oxidative
compounds

Allopurinol, a suicide inhibitor of

xanthine oxidase, to reduce bodily
levels of uric acid

Hydroxycarbamide or Hydroxyurea
induces transcription of gamma
hemoglobin to compensate for lack of
HBB

Hydroxycarbamide or Hydroxyurea
induces transcription of gamma
hemoglobin to compensate for lack of
HBB

Diet management, BH4 cofactor

supplementation

Citrulline supplementation, protein

restriction, arginine supplementation,
benzoic acid, and phenylacetate; liver
transplant

Statins, hypolipidemic agents, and

dietary management

Limit contact sports and other activities

that could exacerbate the aorta

Limit activities that could result in joint

dislocation, as repeated events will
accelerate the arthritic degeneration

Statins, hypolipidemic agents, and

dietary management

Folic acid supplementation while trying

to get pregnant; supplementation must
occur BEFORE you know you are
pregnant, because by that time defects
have already been created

Children with craniosynostosis must

have the sutures surgically reopened
and possibly their skull reconstructed
to avoid risk of brain damage

Limit sunlight exposure

Gleevec (imatinib) is a targeted
tyrosine kinase inhibitor that stops the
rapid proliferation of CML cells,
preventing its progression to "blast
crisis," the terminal phase

Prophylactic salpingoophorectomy,
mastectomy, tamoxifen, herceptin (if
HER2 positive)

Close monitoring, endoscopic polyp

removal, or colectomy if the polyps are
too abundant

Too many polyps to remove

individually; requires colon resection

Treatments discussed in class

short philtrum, down-turned mouth, congenital heart defects, growth retardation and severe mental retardation
eart defects, microcephaly, mental retardation
rowed forehead, death early.
bnormalities, (mental) retardation. Wilms most common.
wide mouth, short palpebral tissues, short upturned nose, long philtrum) CV disease, endocrine abnormalities, prenatal growth deficienc

ar ataxia depletion of Purkinje, prog nystagmus, slurred speech, oculocutaneous telangiectasia, immunodeficiency, death in second decad
lait spots, hypogonadism, microcephaly, hypoplastic or aplastic thumbs, renal malformation, acute leukemia, progressive aplastic anemia
ong narrow face, erythema with telangiectasia in butterfly distribution over nose and cheeks, high pitched voice, small stature, small man

enatal growth deficiency, failure to thrive in infancy, connective tissue ab, mild mental deficiency

, death in second decade of life

gressive aplastic anemia, head and neck tumors
small stature, small mandible, protuberant ears, absence of upper lateral incisors, hypopigmentation and hyperpigmentation, immunodef

d hyperpigmentation, immunodeficiency with decreased IgA, IgM, IgG levels, predisposition to several types of cancer

ypes of cancer