Single gene disorder

pedigree

proband: affected individual that initially comes to light

kindred: relatives outside of the immediate nuclear family

siblings: brothers and sisters of the proband

Single gene disorder

Single gene disorder

single gene inheritance

autosomal dominant

autosomal recessive

X-linked dominant

X-linked recessive

Maternal (mitochondrial) inheritance

Single gene disorder

autosomal dominant: appear in every generation; child of an affected parent has a 50% chance of inheriting the disease; normal members do not transmit the disease

Single gene disorder

autosomal dominant: males and females are equally likely to have the disease and to transmit the disease; male-to-male transmission can occur; males can have unaffected daughters

Single gene disorder

autosomal resseive: parents of an affected individual may not express the disease; the chance of an affected child's brothers or sisters having the disease are 1 in 4; males and females are equally likely to be affected

Single gene disorder

autosomal resseive: a child is at increased risk of a recessive disease if the parents are related

Single gene disorder

X-linked recessive: incidence is much higher in males than females; males do not transmit it to their sons -- they do transmit it to their daughters; sons of these daughters then have a 50% chance

Single gene disorder

X-linked dominant: affected males will not have affected sons; all of their daughters will be affected; sons or daughters of affected females will have a 50% chance of getting the disease

Single gene disorder

Autosomal dominantfamilial hypercholesterolemia (FHC)Huntington's diseaseacondroplasia (short-limbed dwarfism)polycystic kidney diseaseMarfan syndromeneurofibromatosistuberous sclerosis

Single gene disorder

Autosomal recessive

cystic fibrosis (CF)

phenylketonuria (PKU )

alpha-1-antitrypsin (AAT ) deficiency

sickle cell anemia

ADA deficiency

Tay-Sachs disease

hemochromatosis

Single gene disorder

X-linked recessiveDuchenne muscular dystrophyHemophilia AX-linked dominant: only a few, very rare, disorders are classified as X-linked dominanthypophosphatemic rickets (vitamin D -resistant rickets)

Multifactorial disorder

Many of the most common diseases which affect humans undoubtedly involve interactions of numerous genes, including coronary heart disease, hypertension, stroke, and various kinds of cancer.

Multifactorial disorder

Alzheimers disease

heart disease

some cancers

neural tube defects

schizophrenia

insulin-dependent diabetes mellitus

intelligence

Mitochondrial DNA-linked disorder

mitochondria contain their own private DNA; mitochondria come only from the egg; more than 20 hereditary disordersmaternal inheritance; fathers do not pass on the disease

Mitochondrial DNA-linked disorder

appear at any age with a wide variety of non-specific symptoms and signs (metabolic disturbances, developmental delay, blindness, hearing loss, heart rhythm problems, short stature, and gastrointestinal problems)

Chromosome disorder

defect is due not to a single gene, but to an excess or deficiency of the genes contained in a whole chromosome or chromosome segmentDown syndrome is the most common chromosomal disorder (1 out of 800)Klinefelter syndrome (1 out of 1,000 males)Turner syndrome (1 out of 5,000 females)

Chromosomal disorders

aneuploidy in oocytes (18 - 19%) and sperm (3 - 4%)

about 1 in 13 conceptions results in a chromosomally defective conceptus

over 50% of spontaneous abortions during first-trimester are associated with chromosomal anomalies

Chromosomal disorders

chromosomal defects occur in 0.65% of all births; an additional 0.2% of babies were born with balanced structural chromosome rearrangements

5.6 - 11.5% of stillbirths and neonatal deaths have chromosomal defects

Genetic disorders

2 - 3% of children are born with a congenital birth defect

by age 18, approximately 8% are discovered to have one or more anomalies

Frequency of genetic disease by age (per 1000 live births)

type frequency by age 25 lifetime frequency

chromosome disorders 1.8 4

single-gene disorders 3.6 20

multifactorial disease 46.4 646

somatic cell (cancer) disease

- 240

total 52 910

Chromosomal disorder

0.65 - 0.84% of all births

advanced maternal age

75 - 80% of babies with chromosomal defects are delivered by women younger than 35 years of age

Chromosomal disorder

> 50% of first-trimester spontaneous abortions

> 5% of stillborn infants

Chromosomal disorder

Aneuploidy

(trisomy, monosomy, polyploidy)

Deletion

Inversion

Translocation

Insertion

Robertsonian translocation

offspring

parent

Chromosomal disorderIncidence Per 1000 births Per birth

Sex chromosomes

Male 1.15 1/870

Female 0.75 1/1333

Autosomal trisomy 1.42 1/700

Structural abnormality

Unbalanced 0.61 1/1600

Balanced 5.22 1/200

Triploidy 0.02 1/50,000

Total 9.17 1/109

Type of Abnormality Incidence

Numerical aberrations

Sex chromosomes

47,XYY 1/1,000 MB

47,XXY 1/1,000 MB

Other (males) 1/1,350 MB

47,X 1/10,000 FB

47,XXX 1/1,000 FB

Other (females) 1/2,700 FB

Autosomes

Trisomies

13–15 (D group) 1/20,000 LB

16–18 (E group) 1/8,000 LB

21–22 (G group) 1/800 LB

Other 1/50,000 LB

Type of Abnormality Incidence

Structural aberrations

Balanced

Robertsonian

t(Dq;Dq) 1/1,500 LB

t(Dq;Gq) 1/5,000 LB

Reciprocal translocations 1/7,000 LB

Unbalanced

Robertsonian 1/14,000 LB

Reciprocal translocations and insertions 1/8,000 LB

Inversions 1/50,000 LB

Deletions 1/10,000 LB

Supernumeraries 1/5,000 LB

Other 1/8,000 LB

Total 1/160 LB