By : Gan Quan Fu, PT,

MSc Human Anatomy (Batch 3)

Introduction

Classification of Genetic Disorder

Definition & Prevalence

Autosomal Anomalies

Numeric Chromosomal Anomalies

Structural Chromosomal Anomalies

Sex Chromosome Anomalies

Numeric Chromosomal Anomalies

Structural Chromosomal Anomalies

Important definitions in Genetics

Classification of Genetic Disorder

Single gene disorders

Chromosomal Disorder

Autosomal

Numeric Structural

Sex Chromosome

Numeric Structural

Multifactorial Disorder

Acquired Somatic Genetic

Disease

Chromosomal Anomalies = Missing, extra, or

irregular portion of chromosomal DNA.

Most foetus with some chromosomal

abnormality do not survive.

Affects approximately 1 out of 200 of new-

borns.

Karyotype = Full set of chromosomes from an

individual. (Chromosomal Anomalies can be

detected via Karyotype Testing.)

Abnormalities depends on type of chromosome

affected due to non-disjunction chromosomes.

Chromosome affected

Autosomes

Numeric

Autosomal Trisomies

Autosomal Monosomy

Structural

Single Chromosome

Disorder

Two Chromosome

Disorder

Sex Chromosomes

Numeric Structural

Monosomy

Trisomies

Autosomal Anomalies (Numeric)

Monosomy

Single copy of an autosome.

Lethal in early

pregnancy.

Trisomies

Patau Syndrome

(47 + 13)

Edwards Syndrome

(47 + 18)

Down Syndrome

(47 + 21)

An additional chromosome 13 resulting

from nondisjunction during meiosis.

Incidence = 1 in 10,000 -20,000 live

births.

More than 80% die within the first year of

life.

Anomalies can be seen on:

Nervous & Optic System

Musculoskeletal & Cutaneous

Urogenital & Cardiovascular System

Intellectual disability and motor disorder

Microcephaly

Holoprosencephaly (failure of the forebrain to divide properly).

Structural eye defect:

Microphthalmia

Peters anomaly (a type of eye abnormality)

Cataract

Iris and/or fundus (coloboma)

Retinal dysplasia or retinal detachment

Sensory nystagmus

Cortical visual loss

Optic nerve hypoplasia

Meningomyelocele (a spinal defect)

Polydactyly (extra digits)

Cyclopia

Proboscis

Congenital trigger digits

Low-set ears

Prominent heel

Deformed feet known as rocker-bottom feet

Omphalocele (abdominal defect)

Abnormal palm pattern

Overlapping of fingers over thumb

Cutis aplasia (missing portion of the skin/hair)

Cleft palate

Urogenital

Abnormal genitalia

Kidney defects

Cardiovascular

Heart defects (ventricular septal defect &

Patent Ductus Arteriosus)

Dextrocardia

Single umbilical artery

A. Midline defect with

cleft lip & palate.

B. Clenched hand with

overlapping fingers.

C. Postaxial polydactyly.

D.Equinovarus deformity.

E. Punched out aplasia

cutis scalp lesions.

An additional chromosome 18 resulting from

nondisjunction during meiosis.

Incidence =1 in 6000 - 8000 live birth.

Majority of fetuses with this syndrome die

before birth; >90% dead in 1st year.

80% affected were females.

Kidney malformations

Structural heart defects at birth

Ventricular septal defect

Atrial septal defect

Patent ductus arteriosus

Omphalocele (Intestines protruding outside the body)

Esophageal atresia

Intellectual disability

Developmental delays

Growth deficiency

Feeding difficulties

Breathing difficulties

Arthrogryposis (a muscle disorder that causes multiple

joint contractures at birth)

Small head (microcephaly) accompanied by a prominent back portion of the head (occiput),

Low-set, malformed ears,

Abnormally small jaw (micrognathia),

Cleft lip/cleft palate,

Upturned nose,

Narrow eyelid folds (palpebral fissures),

Widely spaced eyes (ocular hypertelorism),

Drooping of the upper eyelids (ptosis),

A short breast bone,

Clenched hands

Choroid plexus cysts

Underdeveloped thumbs and/or nails

Absent radius

Webbing of the second and third toes, clubfoot or rocker bottom feet

Males will have undescended testicles.

An additional chromosome 21 resulting from nondisjunction during meiosis. (*Extra chromosome 21 in every cell of the body)

John Langdon Down (the British physician) who described the syndrome in 1866.

Karyotype = 47,XX+21 or 47,XY+21

Characteristics Percentage Characteristics Percentage

Mental impairment 99% Abnormal teeth 60%

Stunted growth 90% Slanted eyes 60%

Umbilical hernia 90% Shortened hands 60%

Increased skin back

of neck80% Short neck 60%

Low muscle tone 80%Obstructive sleep

apnea60%

Narrow roof of

mouth76% Bent fifth finger tip 57%

Flat head 75%Brushfield spots in

the iris56%

Flexible ligaments 75%Single transverse

palmar crease53%

Large tongue 75% Protruding tongue 47%

Abnormal outer ears 70%Congenital heart

disease40%

Flattened nose 68% Strabismus ~35%

Separation of first

and second toes68%

Undescended

testicles20%

Can happen in a chromosome itself,

the other is not required.

Deletion

(Genetic material

missing)

Duplication

(Genetic material

present twice)

Inversion

(Genetic material is

“flipped”)

Need 2 chromosomes to occur these

processes.

Insertion

(Genetic material is added from

another chromosome)

Translocation

(Material is swapped(exchanged)

with another chromosome)

Name is based on the infant’s cry. (high-

pitched and sounds like a cat.)

Incidence =1 in 216,000 birth

Normal 46 chromosomes but, missing a piece

of chromosome number 5.

Most cases are believed to occur during the

development of the egg or sperm, small

number of cases occur when a parent passes

a different, rearranged form of the

chromosome to their child.

Cry is high pitched and similar to that of a meowing kitten.

Moon-shaped face

Malformed larynx

Difficulty swallowing and sucking (Feeding Problem).

Low birth weight and poor growth.

Severe cognitive, speech, and motor delays, mental retardation

Behavioural problems such as hyperactivity, aggression, and repetitive movements.

Excessive drooling(ptyalism)

Chromosome affected

Autosomes

Numeric Structural

Sex Chromosomes

Numeric

Autosomal Trisomies

Autosomal Monosomy

Structural

X-link Dorminant

X-link Recessive

Sex Chromosome Anomalies (Numeric)

Monosomy

Turner’s syndrome

(45,X0)

Trisomies

Klinefelter'ssyndrome

(47,XXY)

Jacob’s syndrome

(47,XYY)

Triple x syndrome

(47,XXX)

Sex chromosomal monosomy(45, XO)

99% of foetuses with Turner syndrome result

in spontaneous termination during the first

trimester.

Incidence = 1 in 2000-5000.

Short stature

Skeletal disorders (osteoporosis which may lead to scoliosis)

Webbed neck(due to cystic hygroma)

Broad shoulders

Broad chest (shield chest), widely spaced nipples

No/Poor breast development

Narrow hips (High waist-to-hip ratio: hips are not much bigger than waist)

Lymphedema of hands and feet

Shortened metacarpal IV

Cubitus valgus

Underdeveloped ovaries(streak gonads,

hence this syndrome also called ovarian

dysgenesis)

Sterile, lack expected secondary sex

characteristics

Amenorrhoea(No menstruation)

Cardiovascular problems (Coarctation of the

aorta, Bicuspid aortic valve)

Horse shoe kidney

Thyroid problems (hypothyroidism

specifically Hashimoto's thyroiditis).

XXY Males

Disorder occurring due to nondisjunction of the X chromosome during Meiosis. Extra X chromosome is nondisjunction during

meiosis II of the germ cell in the female.

Occur when sister chromatids on the X sex chromosome fail to separate.

XX ovum produced and when fertilized with a Y-sperm it yields XXY offspring.

Also occurs X and Y sex chromosomes fail to separate, producing a sperm with an X and Y chromosome & fertilize with normal X ovum produces XXY offspring.

Incidence = 1 in 500 live male births.

48, XXYY (male) syndrome

Incidence = 1 in 18,000–40,000 births

48,XXXY

Incidence = Extremely rare

Childhood Weaker muscles and reduced strength.

Puberty (features become more prominent due to

hypogonadism (less amount of testosterone produced): Rounded body type Broader hips Little body hair is present Gynecomastia (increased breast tissue) Microorchidism (i.e. small testicles) Azospermia leading to infertility Micropenis Tall stature IQ is normal

Characterized by the presence of an additional Y chromosome.

Incidence = 1 in 1,800 births

Features Present: Normal physically

Normal mentally

Increase in testosterone

More aggressive

Normal lifespan

There are article which claims that those with Jacob’s Syndrome are more prone in committing crime.

Characterized by the presence of an additional X

chromosome.

When an XX ovum fertilizes with X- sperm.

Incidence = 1 in 1,000 birth

Features Present

Normal physically, Sometimes taller.

Normal mentally, Increase risk of retardation

and learning difficulties.

Fertile.

Genotype Gender Syndrome Physical Traits

XY Male -

XXY

XXYY

XXXY

Male Klinefelter’s

Syndrome

sterility, small testicles,

breast enlargement

XYY Male XYY or Jacob’s

Syndrome

normal male traits

XX Female -

XO Female Turner Syndrome sex organs don’t mature

at adolescence, sterility,

short stature

XXX Female Triple X tall stature, learning

disabilities, limited fertility

Sex Chromosome Anomalies (Structural)

Y-Linked Disease

Very Rare

X-Linked Disease

X-Linked Dominant

X-Linked Recessive

Also known as ‘holandric inheritance’.

Determination of a phenotypic trait by an allele (or gene) on the Y chromosome.

Pass from father to son with no interchromosomal genetic recombination

Very rare.

Deletion (missing genetic materials) in Y-gene is a frequent genetic cause of male infertility.

Having hairy ears was once thought to be a Y-linked trait in humans, but that hypothesis has been discredited.

Single gene disorders that reflect the presence of defective genes on the X chromosome.

Show inheritance patterns that differ from autosomal diseases.

Male have one X chromosome + a Y chromosome while females have 2 X chromosome, they show different patterns of inheritance and severity of manifestation. (There are both dominant and recessive X-linked diseases, also there are some characteristics that are common to X-linked disorders in general).

Males are never carriers, if they have a mutated gene on the X chromosome, it will be expressed.

Males are termed hemizygous for genes on the X chromosome.

Expressed in females when only a single copy of the mutated

gene is present.

Very few diseases have been identified:

Alport syndrome

Nephrogenic Diabetes Insipidus

Hypophosphatemic rickets or vitamin D resistant rickets

(leading to low serum phosphorus & skeletal abnormalities)

Never passed from father to son.

Affected males produce only affected females. (An affected male

only has one X chromosome to pass on to his daughters.

Affected females produces 50% normal and 50% affected

offspring. (Heterozygous).

Males are usually more severely affected than females. Some X-

linked traits may even be lethal.

Females are more likely affected. (They have 2x increase risk to

inherit the mutated allele, since they have 2X chromosomes)

Inherited, heterogeneous disorders involving basement membranes of kidney, frequently affecting the cochlea and eyes.

Clinical Manifestation:

Renal Hematuria

Proteinuria

Hypertension with edema and nephrotic syndrome at later stage.

Hearing Sensorineural deafness (90% are deaf by age of 40 years)

Ocular Dot-and-fleck retinopathy

Leiomyomatosis

Diffuse leiomyomatosis of the esophagus and tracheobronchial tree

Occurs when the kidneys cannot concentrate

urine normally resulting excretion of large

amount of dilute urine. *Kidney tubules do not

respond to Antidiuretic Hormone (ADH).

Very Rare

Symptoms

Intense or uncontrollable thirst, and crave

ice water.

Produce large amounts of urine (usually

more than 3 liters, and up to 15 liters per

day.)

Easily dehydrated

Form of rickets characterized by low serum phosphate levels.

Resistance to treatment with ultraviolet radiation or vitamin D ingestion.

Incidence = 1 in 20,000 newborns

Symptoms: Short stature

Associated with this condition is disproportionate, resulting from deformity and growth retardation of the lower extremities.

Bow Legged and deformities associated with bones

Bone Pain and Joint Pain

Hereditary pattern which a recessive gene in X chromosome results in:

Male : Manifestation of characteristics

Female : Carrier (Usually)

Males are more likely affected, they only need one copy of mutant allele to express phenotype.

Female must have 2 copies of the mutant allele in order for the mutant phenotype to develop.

Female with 1 copy of the mutant allele is only a carrier.

Disorders are:

Colour blindness

Duchenne Muscular Dystrophy

Hemophilia

Also known as colour vision deficiency (CVD).

Trouble seeing

Red

Green

Blue

Mix of colours mentioned above.

Rarely that a person sees no color at all.

Three types of cone cells in eye (each type senses either red, green, or blue light most concentrated in macula). Individuals with colour blindness do not have these cone cells.

Incidence = Approximately 1 in 12 men (8%); 1 in 200 women

Form of muscular dystrophy (muscle

weakness and loss of muscle tissues) which

worsens quickly.

Caused by a defective gene for dystrophin (A

type of protein in muscles).

Incidence = 1 in 3,600 male infants

Usually appear before age 6 and may appear as early as infancy.

Include:

Fatigue

Learning difficulties (IQ can be below 75)

Intellectual disability

Muscle weakness:

Begins in the legs and pelvis less severe in the arms, neck, and other areas of the body

Problems with motor skills (running, hopping, jumping)

Frequent falls

Trouble getting up from a lying position or climbing stairs

Weakness quickly gets worse

Progressive difficulty walking:

Ability to walk may be lost by age 12

Breathing difficulties and heart disease usually start by age 20

Blood fails to clot normally

Lacking a blood clotting factor VIII (antihemophilic globulin, AHG), IX (ChrismasFactor).

Bleeding from even minor cuts

Incidence = 1,500 newborn males.

Hemophilia A = Lack of clotting factor VIII. 75% occurrence.

Hemophilia B = "Christmas Disease" is a defect in clotting factor IX.

Transfusions of fresh whole blood or plasma or factor to control bleeding

Also known as Martin-Bell syndrome; Marker X syndrome.

Some consider this syndrome as X-linked dorminant, some consider this as X-linked recessive which some claims this to be not under X-linked dorminant or recessive.

Genetic condition involving changes in the long arm of the X chromosome.

Characterized by mental retardation.

Fragile area on X chromosome tends to repeat bits of the genetic code. (*More repeats, the more likely there is to be a problem.)

Male and female can both be affected.

Male have only one X chromosome, single fragile X more likely to affect them more severely.

Family history of fragile X syndrome,

especially a male relative

Mental retardation

Large testicles (macro-orchidism)

Large size

Tendency to avoid eye contact

Hyperactive behaviour

Large forehead and/or ears with a prominent

jaw

Aneuploidy = Addition or loss of one (rarely two) chromosome. Trisomy = 3 copies of a chromosome, (2n+1)

Tetrasomy = 4 copies of a chromosome, (2n+2)etc

Monosomy = 1 member of a chromosome pair missing, (2n-1) that is only single copy of a chromosome is present.

Euploidy = Normal condition, where the genotype consists of complete two sets of chromosomes (23+23 or 2n).

Genotype = Genetic make up of cell.

Karyotype = Number and appearance of chromosome in a nucleus.

Non disjunction = Incorrect separation of chromosomes or sister chromatids during meiosis.

Phenotype = Characteristics of an Organism

Polyploidy = Entire extra set of chromosomes present, [can be triploidy(3n= 69 chromosomes),tetraploidy(4n=92 chromosomes) etc.]