List of Genetics Disorders

Disease Name

Hemophilia (classic)

Ornithine Transcarbamylase Deficiency

Fragile X

Glucose Phosphate Dehydrogenase Deficiency

(Favism)

Lesch Nyhan Syndrome

Diseases - X linked

Duchenne Muscular Dystrophy

Androgen Insensitivity Syndrome

Rett Syndrome

MELAS

Diseases - X linked

Diseases - Mitochondrial

MERRF

Cystic Fibrosis

Sickle Cell Anemia

Beta-Thalassemia

Alpha-Thalassemia

Diseases - Mitochondrial

Diseases - Autosomal recessive with

heterozygote advantage

Phenylketonuria

Ornithine Transcarbamylase Deficiency

Tay Sachs Disease

Familial Hypercholesterolemia

Diseases - Inborn errors of metabolism

Marfan Disease

Ehlers-Danlos

Diseases - Autosomal dominant

(negative)

Osteogenesis Imperfecta

Huntington's Disease

Achondroplasia


(negative)

Familial Hypercholesterolemia

Limb-Girdle Muscular Dystrophy

Praeder Willi

Angelman Syndrome

Diseases - Examples of imprinting


(negative)

Patau Syndrome

Edwards Syndrome

Down Syndrome

Diseases - Chromosomal

Turner Syndrome

Triple X Syndrome

Kleinfelter's Syndrome

XYY


DiGeorge Syndrome

Alzheimer's Disease

Autism

Gastroschisis


Diseases - Complex genetic

Diseases - Errors in development

Treacher Collins Syndrome

Diaphragmatic Hernia

Pulmonary Hypoplasia


VACTERL

Esophageal Atresia


Tracheal-esophageal Fistula

Polydactyly

Holoprosencephaly


Exencephaly/anencephaly and Spina Bifida



ASD (Atrial Septal Defect)

VSD (Ventricular Septal Defect)


ASD (Atrial 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

Retinoic Acid Embryopathy

Diseases - Fetal teratogenic


Fetal Thalidomide Exposure

Xeroderma Pigmentosum

CML (Chronic Myelogenous Leukemia)

Neurofibromatosis

Breast Cancer

Diseases - Fetal teratogenic

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

Diseases - Cancer related mutations

Ataxia-telangiectasia

Fanconi anemia

Bloom syndrome

Type of Mutation 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

Nonspecific loss of function X-linked Recessive

HGPRT protein

(hypoxanthine-

guanine

phosphoribosyl

transferase)


Dystrophin

gene


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 Varying genes

Point mutation, loss of function Mitochondrial tRNA Lys

Most common is ΔF508, many

different etiologies Autosomal recessive CFTR

Missense Mutation E6V Autosomal recessive

HBB

(hemoglobin B)

Mutation that reduces hemoglobin

production or stability; found in

promoters, splice sites, and 3'/5'

UTRs

Autosomal recessive; may

be compound heterozygous

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

Nonspecific loss of function Autosomal Recessive

Hexosaminidas

e A

Nonspecific loss of function Autosomal dominant

Usually in LDLR

gene (LDL

receptor

protein)

Loss of function that does not

impede expression

Autosomal Dominant

Negative

Fibrillin protein

FBN1


impede expression

Autosomal Dominant

Negative

Collagen

proteins

(COL;1/3/5;A1/

2


impede expression

Autosomal Dominant

Negative (except for 3 of the

collagen associated protein

mutations)

Various

proteins,

usually type 1

Collagen

protein COL1A1

or COL1A2 or

associated

proteins

CAG trinucleotide repeat; affected

by anticipation Autosomal Dominant HTT gene

Gain of function mutation Autosomal Dominant

FGFR3

(Fibroblast

Growth Factor

Receptor 3)

Nonspecific loss of function Autosomal dominant

Usually in LDLR

gene (LDL

receptor

protein)

Activation of a cryptic splice donor

site resulting in frame shift

Autosomal dominant or

recessive Calpain 3 gene

Deletion of paternal PWS segment

of chromosome 15 or maternal

uniparental disomy

Maternally imprinted;

Paternally

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

Paternally imprinted;

Maternally

inherited/expressed

More than one

gene is

expressed in

this region;

chromosomal

abnormality

Trisomy 13

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

Trisomy 18



from a balanced

translocation, from de novo

imbalanced translocation, or

from a germline



Trisomy 21



from a balanced

translocation, from germline

de novo imbalanced

translocation, from

robertsonian translocation,

or from germline



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

reproductively fit and may

pass on their own deletions

Chromosomal

22q deletion

involving Tbx1

Complex genetic disorder with

multiple loci and allele involvement

Not inherited in Mendelian

fashion; may be familial

multifactorial inheritance Unknown


multiple loci and allele involvement



multifactorial inheritance Unknown

Unknown; may be due to various

mutations



multifactorial or arise from

de novo mutations in

germline Unknown


Seems to be mostly de novo

mutations, but the disease

does not cause infertility

TCOF1 gene

encoding the

treacle protein


mutations





germline

Many cases

may be due to

insufficiency in

retinoic acid

signaling

pathways


mutations





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


mutations





germline

It is one of the

possible effects

of a disrupted

Shh signaling

pathway


mutations





germline

It is one of the

possible effects

of a disrupted

Shh signaling

pathway

Suspected to be loss of function in

Shh regulatory protein Unknown

Associated with

Gli3 mutations

affecting the

Shh signaling

pathway


mutations





germline

Unknown, but

most likely due

to Shh signaling

pathway

(possibly Gli2)


multiple alleles



multifactorial inheritance

Unknown; it

may be related

to the Shh

pathway

(VACTERL)

Tbx1 and Shh

signaling

pathway

components or

regulators, also

present in

retinoic acid

embryopathies

Some causes are inherited in

an autosomal dominant

manner

Known causes include

chromosomal deletions and

genetic mutations that cause loss

of function

Same as ASD Same as ASD Same as ASD

Tbx1 and Shh

signaling

pathway

components or

regulators, also

present in

retinoic acid

embryopathies

Some causes are inherited in

an autosomal dominant

manner

Known causes include

chromosomal deletions and

genetic mutations that cause loss

of function

Same as ASD Same as ASD Same as ASD

Same as ASD, as far as I can tell

Same as ASD, as far as I can

tell

Same as ASD,

as far as I can

tell (present in

VACTERL,

DiGeorge, and

Retinoic Acid

Embryopathy)

Same as ASD, as far as I can tell

Same as ASD, as far as I can

tell

Same as ASD,

as far as I can

tell

Trisomy 21, DiGeorge deletion,

mutations related to Shh Varies

Trisomy 21,

Tbx1 deletion,

mutations

related to Shh

May be due to various kinds of

mutations, both loss of function

and gain of function

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

reproductively fit and may

pass on their own deletions

Chromosomal

22q deletion

involving Tbx1

Nonspecific loss of function Autosomal dominant Tbx5

Not genetic; caused by etoh

consumption in pregnancy

Not genetic; caused by etoh

consumption in pregnancy

Causes

downregulation

of Shh and

retinoic acid

Not genetic; caused by excess

retinoid intake during pregnancy,

notably from acutane

Not genetic; caused by

excess retinoid intake during

pregnancy, notably from

acutane

Retinoids are

converted into

retinoic acid,

mimicking

upregulation of

RALDH genes

Not genetic; caused by thalidomide

intake during pregnancy

Not genetic; caused by

thalidomide intake during

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 Usually a de novo mutation

T (9;22) fusion

of Bcr and Abl


Autosomal recessive; as if

autosomal dominant due to

high rate of loss of

heterozygosity; highly

varying expressivity and

severity NF1



autosomal dominant with

45-60% penetrance BRCA1/BRCA2



autosomal dominant with a

varying penetrance; 90% in

males, 70% in females Various Genes




70% Loss of Heterozygosity APC




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

Type of Mutation Mode of Inheritance

Gene/Locus/Lo

cation

4p16.3 deletion WHCR

5p15.2 deletion, CDCCR, CLCR

17p13.3 microdeletion, LIS1 gene, 14-3-3e gene

11p13 microdieletion WT1 gene, PAX6 gene

7q11.23 microdeletion 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 Clinical Presentation

Coagulation of blood

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

Severe mental retardation; long face; large

ears; prominent jaw; macroorchidism

(congenital giant gonads)Loss of G6PD function;

first step of pentose

phosphate shunt

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

Dystrophin is thought to

participate in a complex

that plays a role in linking

the cytoskeletons of

muscle fibers with the

extracellular matrix

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

tissue; boys are often wheelchair bound by

their teen years, and life expectancy is

about 25-30 upon gradual paralysis of the

neck, shoulders, heart and diaphragm; later

symptoms inclute spine or other bone

deformities

Loss of function of

androgen receptor protein

results abnormal male

development; severity is

based on how poor

receptor function is

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

male or female, sometimes called a

"hermaphrodite" but that may be perceived

as a negative label

In reduced insensitivity: may develop

external male genetalia, but with

hypospadius, cryptorchidism, or infertility

Loss of MECP2 function,

disrupting the DNA

methylation pathway

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

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

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

Nonfunctioning tRNA Lys

results in the inability to

produce mitochondrial

proteins necessary for TCA

and Ox-Phos

Myoclonic Epilepsy with Ragged Red Fibers;

Progressive myoclonic (muscular) epilepsy;

ragged red fibers - aggregations of diseased

mitochondria in subsarcolemmal region of

muscle fibers; short stature; hearing loss;

lactic acidosis; exercise intolerance; poor

night vision

Poor Cl transporter

activity; insufficient

transcription; poor

trafficking of Cl trasporter;

functional protein but

rapid degredation

Commonly, pancreatic insufficiency;

gastrointestinal/nutritional insufficiency;

high salt loss through sweat; chronic

bronchopulmonary infection; sometimes

infertility; frequency varying by population -

1/29 in Ashkenazi Jews, 1/28 in N.

Americans of N. European descent, and

1/61 in African Americans

Hypoxic state causes HBSS

to partially denature and

form an aggregate

Low oxygen states cause hypertension,

anemia, stroke, and ischemic pain; ischemia

of the spleen requiring splenectomy is

common at a young age; septicemia risk in

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

Deficiency in PAH

prevents conversion of

phenylalanine to tyrosine,

which at increased

concentrations is toxic to

the brain

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

is INCREDIBLY difficult - must completely cut

out all meat, eggs, legumes, dairy, and most

grains, can mostly only eat fruits and

vegetables with awful tasting protein

supplements; a single day of poor eating can

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

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 birthA 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

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

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

Expression of bad fibrillin

gene interferes with

normal protein function,

has widespread systemic

effects

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

eye, decreased pupillary miosis (constriction

response)

Cardiovascular: [dilation of the ascending

aorta involving the sinuses of valsalva,

dissection of ascending aorta]; mitral valve

Expression of bad collagen

protein interferes with

normal collagen function,

can affect many parts of

the body

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

issues including arterial dissections and

intestinal rupture, abnormal facies with

large protruding eyes and thin face,

transluscent skin, and prone to collapsed

lungs

Expression of bad collagen

protein interferes with

normal collagen function,

can affect many parts of

the body

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

the time; symptoms include loose joints,

spinal curvature, poor muscle tone, slight

protrusion of the eyes with grey blue sclera,

easily fractured bones, and possibly early

hearing loss

CAG (polyglutamine)

repeat causes some HTT

to misfold; misfolded

proteins aggregate within

neurons, preventing them

from being destroyed;

aggregation leads to

neuronal death and

plaque formation

Risk determined by number of repeats: <26,

normal; 27-35, risk for offspring; 36-39, at

risk, reduced penetrance; 40-55, adult

onset; >55, juvenile onset(prior to age 20);

in rare cases, may occur in children;

symptoms include changes in memory and

behavior, particularly an increase in ager or

violence, depression, mania, and OCD;

inability to perform job duties; gradual loss

of motor control, muscle movement,

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,

so it is common for both

to be deleted together

Hypotonia, poor development, short

stature, small hands and feet, mental

retardation, polyphagia, obesity is common

Multigene syndromes

largely affecting the brain;

PWS genes and AS genes

are geographically very

close in the chromosome,

so it is common for both

to be deleted together

Extremely happy demeanor, waving of

hands and forearms with limp wrists and

bent elbows like marionettes

Extra copy of

chromosome 13 causes

disease state due to gene

dosage effects

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

palate, low set ears, missing skin or hair;

abnormal genitalia and kidney defects;

heart defects

~80% of patients die by age 1

Extra copy of



dosage effects

Microcephaly; low set, malformed ears;

micrognathia and cleft lip and/or palate

(classical cleft or Pierre-Robin sequence);

ocular hypertelorism with narrow palpebral

fissures and ptosis; cryptorchidism

Extra copy of



dosage effects

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

infections, altered leukemia risks,

hypothyroidism, increases risk of seizures

and Alzheimer's, pointed cornea, and

standing eversion of the feet

Monosomy of the

pseudoautosomal regions

of the X chromosome

results in

haploinsufficiency

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

menstruation

Other symptoms include possible coarcation

of the aorta, infertility due to premature

degeneration of ovaries, and kidney

abnormalities

Trisomy of the

pseudoautosomal regions

of the X chromosome

causes only minor, usually

unnoticeable phenotypic

changes and few health

complications; often

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 cellsTwo copies of X

chromosome in males

results in androgen

deficiency, affecting

develompent of

secondary sex traits;

typically not diagnosed

until puberty

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

Like XXX; very minor

phenotypical changes,

often going undiagnosed

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

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)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

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 deteriorateSeems 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

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

thresholdUnknown cause, but cell

migration and lateral

folding is disrupted,

resulting in failure to close

ventral wall

Viscera of the body, including the heart,

may be exposed

Disruption of TCOF1

causes massive apoptosis

of neural crest cells in the

first branchial arch via an

unknown mechanism

This mutation results in hypoplasia of the

mandible and facial bones resulting in

narrow face and no zygomatic processes;

low, malformed external and middle ears;

very small chin that may lead to high or cleft

palate and teeth probems; sagging or

drooping lower eyelids due to lack of

underlying structuresUnknown mechanism, but

cell migration of

pleuroperitoneal folds

from the the body wall to

form the diaphragm is

disrupted, resulting in a

connected

pericardioperitoneal

cavity

Lung and heart development may be

impaired due to herniation of abdominal

viscera into the thoracic cavity; presence of

diaphragmatic hernia and pulmonary

hyperplasia may be indicative of retinoic

acid insufficiency

Retinoic acid is not only

responsible for anterior-

posterior 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 tracheal-

esophageal 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

Unknown cause, but

suspected to be disrupted

Shh signaling causing

midline neural and

craniofacial patterning to

be disrupted

Midline brain and craniofacial defects that

usually result in the absence of normal

structures and vary in severity from very

mild brain malformations and normal facies

to severe: cyclopea; absence of nasal

septum; single nostril; single incisor; cleft

lip; single small cerebral hemisphere due to

incomplete division of the forebrain

Exencephaly/anencephaly

and spina bifida are

caused by incomplete

closure of the neural tube

during development at

the head and most

commonly the lumbar

spine, respectively

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

amniotic fluid and begins degredation;

others may have exposed dural sacs that

have herniated out of lesions, or they may

even be too small for that to occur (spina

bifida occulta); in severe cases, the children

are paralyzed, in less severe cases they are

normal with surgical repair, in the most mild

there is no intervention necessary

Atrial septal defects can

arise from abnormalities

in Shh signaling (VACTERL)

causing improper

migration to the heart to

form septal structures

They may also arise from

abnormalities in

secondary heart field cells

(DiGeorge Tbx1 deletion)

that may result in poor

migration, differentiation,

or survival (unknown

mechanism)

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

for the heart to flow through

An atrial septal defect is a local defect in

atrial septation that causes mixing of

oxygenated and deoxygenated blood; after

birth, the left side of the heart becomes

higher in pressure than the right, causing

blood to flow from left atrium to right

atrium

A similar, but more severe defect in

development is a common atrium where

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

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

Retinoic acid

embryopathy also causes

ASD as retinoic acid plays

a role in neural crest

migration to the AV

cushions that form the

bottom of the atrial

septum- these neural

crest cells apoptose and

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


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

membranaceae)

VSD causes shunting of oxygenated blood

from the left ventricle to the right ventricle

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

for the heart to flow through

An atrial septal defect is a local defect in

atrial septation that causes mixing of

oxygenated and deoxygenated blood; after

birth, the left side of the heart becomes

higher in pressure than the right, causing

blood to flow from left atrium to right

atrium

A similar, but more severe defect in

development is a common atrium where

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

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

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

are possible causes for

persistent truncus

Outflow tract is not separated into

pulmonary artery and aorta; lack of growth

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

Cause of tetralogy of

Fallot in Down syndrome

patients was never

discussed, but the cardiac

disruption speaker

mentioned their

association; causes for

other mutations are

similar to those for ASD

and VSD

Tetralogy of Fallot consists of 4

malformations:

1) Overriding aorta

2) Ventricular septal defect

3) Pulmonary stenosis

4) Right ventricle hypertrophy, which I

believe is secondary to narrowed pulmonary

artery and resultant pulmonary

hypertension

In tetralogy of Fallot, the conal septum is

deviated, creating all four characteristic

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

disrupted proximal-distal

patterning;

Any number of digits may be fused with

varying severity; in extreme cases, all five

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)

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 headHox13 is expressed

caudally and distally on

appendages; loss of

appropriate expression or

function results in

improper development of

these regions

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

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


and development of

pharyngeal arch and

pouch structures, possibly

due to problems in neural

crest cell migration

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 ("heart-

hand 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

Thalidomide poisoning in the embryo

results most notably in truncation of the

limbs; additional deformities include those

of the eyes, hearts, gut, and urogenital

tractsLoss of function of XP

results in reduced

efficiency of nucleotide

excision DNA repair

mechanism in response to

UV light induced

pyrimidine dimers

Sensitivity to sunlight, unusually high

number of freckles, irregular dark spots on

the skin, sensitive eyes

Fusion of the two proteins

creates a constitutively

active tyrosine kinase that

activates many proteins in

the cell

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

Loss of neurofibromin

protein results in

unchecked neuronal cell

growth

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

dsDNA breaks are

repaired less efficiently

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

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 pregnancyAPC no longer causes B-

catenin degredation,

which then builds up

freely in the cell and

induces

MYC(protooncogene)

expression

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

induce progression

through cell cycle

Germline mutation results in an incredibly

high risk for bilateral retinoblastoma tumors

of the eyes, requiring removal of the eyes

Loss of "guardian of the

genome;" Cells with

damaged genomes no

longer arrest their cell

cycles or apoptose

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

of the body; the most common kinds are

breast cancers, brain tumors, acute

leukemias, soft tissue sarcomas,

osteosarcomas, and adrenal cortical

carcinomas

Function Altered Clinical Presentation

Prominent forehead broad nasal root, short philtrum, down-turned mouth, congenital heart defects, growth retardation and severe mental retardation

Round faces, catlike cry, congenital heart defects, microcephaly, mental retardation

Lissencephaly, microcephaly, high furrowed forehead, death early.

WT1 gene, PAX6 gene Wilms tumor, anridia, genitourinary abnormalities, (mental) retardation. Wilms most common.

WBSCR, ELN gene, LIMK1 gene facial dysmorphology (prominent lips, wide mouth, short palpebral tissues, short upturned nose, long philtrum) CV disease, endocrine abnormalities, prenatal growth deficiency, failure to thrive in infancy, connective tissue ab, mild mental deficiency

DNA recomb repair enzymes, 11q22 ATM gene ionizing radiation sensitivity, cerebellar ataxia depletion of Purkinje, prog nystagmus, slurred speech, oculocutaneous telangiectasia, immunodeficiency, death in second decade of life

DNA recomb repair enzymes, 16q24, FA-A gene crosslinking agent sensitivity, café-au-lait spots, hypogonadism, microcephaly, hypoplastic or aplastic thumbs, renal malformation, acute leukemia, progressive aplastic anemia, head and neck tumors

DNA repair enzymes, 15q26, BLM gene hypersensitivity to damaging agents, long narrow face, erythema with telangiectasia in butterfly distribution over nose and cheeks, high pitched voice, small stature, small mandible, protuberant ears, absence of upper lateral incisors, hypopigmentation and hyperpigmentation, immunodeficiency with decreased IgA, IgM, IgG levels, predisposition to several types of cancer

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

Prominent forehead broad nasal root, short philtrum, down-turned mouth, congenital heart defects, growth retardation and severe mental retardation

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 nose, long philtrum) CV disease, endocrine abnormalities, prenatal growth deficiency, failure to thrive in infancy, connective tissue ab, mild mental deficiency

ionizing radiation sensitivity, cerebellar ataxia depletion of Purkinje, prog nystagmus, slurred speech, oculocutaneous telangiectasia, immunodeficiency, death in second decade of life

crosslinking agent sensitivity, café-au-lait spots, hypogonadism, microcephaly, hypoplastic or aplastic thumbs, renal malformation, acute leukemia, progressive aplastic anemia, head and neck tumors

hypersensitivity to damaging agents, long narrow face, erythema with telangiectasia in butterfly distribution over nose and cheeks, high pitched voice, small stature, small mandible, protuberant ears, absence of upper lateral incisors, hypopigmentation and hyperpigmentation, immunodeficiency with decreased IgA, IgM, IgG levels, predisposition to several types of cancer

facial dysmorphology (prominent lips, wide mouth, short palpebral tissues, short upturned nose, long philtrum) CV disease, endocrine abnormalities, prenatal growth deficiency, failure to thrive in infancy, connective tissue ab, mild mental deficiency

ionizing radiation sensitivity, cerebellar ataxia depletion of Purkinje, prog nystagmus, slurred speech, oculocutaneous telangiectasia, immunodeficiency, death in second decade of life

crosslinking agent sensitivity, café-au-lait spots, hypogonadism, microcephaly, hypoplastic or aplastic thumbs, renal malformation, acute leukemia, progressive aplastic anemia, head and neck tumors




Documents

List of Genetics Disorders