Genetic diseases affect all populations and have been apparent since prehistory.

7,5% of all conceptions have a chromosomal abnormality.Majority of these are lost as early spontaneous miscarriages

3% of newborn have congenital malformations, with geneticcauses at least one third of all malformations.

Nearly one –half stillbirth and 20% of early neonatal deathsare atrributable to major congenital malformations.

Genetic disease now causes about one-half of all deathin chilldhood and accounts for one-third of all pediatric

hospital admissions

Chronic diseases with significant genetic component affect10-20% of the adult population

Common reasons for referral to a genetic clinic

Genetic disease diagnosed, counselling requested

Testing carrier state of family members for mendelian disorders

Investigation and diagnosis of possible genetic disease

Diagnosis of mental handicap of physical abnormality

Diagnosis of malformation in neonates or stillbirth

Genetic management of high risk pregnancies

Interpretation of abnormal prenatal tests

General populations risks

Spontaneous miscarrige 1 in 6

Perinatal death 1 in 30-100

Major congenital malformation 1 in 33

Serious mental or physical handicap 1 in 50

Adult cancer 1in 4

Prevalence of genetic disease

Type of genetic disease Estimated prevalence per 1000population

Single gene: autosomal dominant 2-10autosomal recessive 2X-linked recessive 1-2

Chromosomal abnormalities 6-7

Common disorders with appreciablegenetic component 7-10

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Dysmorphology

Dysmorphology is the study of malformation arising from abnormal embryogenesis. Recognition of patterns of multiple congenital malformations may allow inferences to be made about timing, mechanism and aetiology of structural defects.

Malformation

A malformation si a primary structural defect occuring duringdevelopment of an organ or tissue. Most single malformations are inherited as polygenic traits with a low risk of recurrence. Multiple malformation syndromes comprise defects in two or more systems and are often associated with mental retardation. The risk of recurrence is determined by aetiology (chromosomal, teratogenic, mutation of a single gene or unknown).

Aethiology of major congenital malformation

Idiopathic 60%

Multifactorial 20%

Monogenic 7,5%

Chromosomal 6%

Maternal illness 3%

Congenital infections 2%

Drug, X-ray, alcohol 1,5%

Major congenital malformations

Single major congenital malformations are presentin 3 % of neonates

Examples of major congenital malformations

Cleft lip and palate

Congenital heart defects

Neural tube defects

Abnormalities of urogenital tract

Minor congenital malformations

Examples

Epicanthic folds

Mongoloid or antimongoloid slant

Coloboma

Ear tag or pit

Bifid uvula

Soft tissue syndactyly

Simian crease

Minor congenital malformations

Minor congenital malformations

Deformation

Deformation are caused by any factor which restricts mobility of the fetus and so causes prolonged compression in an abnormal posture. Causes may be intrinsic or extrinsic. Deformation usually involve musculosceletal system and may occur in fetuses with congenital neuromuscular problems.

Causes of congenital deformation

Intrinsic: neuromuscular disease, connective tissue defectsCNS malformation

Extrinsic: primigravidae, small maternal stature, oligohydramnions uterine malformation, breech position, multiplepregnancy

Type of congenital deformation

Congenital dislocation of the hip

Congenital postural scoliosis

Plagiocephaly

Torticollis

Mandibular asymmetry

Disrupton

A disruption defect implies that there is destruction of a part of a fetus that had initially developed normally. As the fetus is generally normal and the defects are caused by an extrinsic abnormality the risk of recurrence is small.

Aetiology

Interruption of the blood supply

Amniotic band disruption after early rupture of the amnioncausing constriction bands and amputations of digits and limbs, more extensive disruptions causing facial clefts and central nervous systém defects.

Examples of amniotic band disruption

Sequence

the term implies that a series of events occure after a single initiating abnormality, which may be a malformation,

a deformation or a disruption

Potter sequence – initial abnormality is renal agenesis, whichgives rise to secondary deformation and pulmonary hypoplasia

AssociationCertain malformations occur together more often

than expected by chance alone.Vater associations consists of vertebral anomalies, anal atresia, tracheo-oesophageal fistula, radial defects

Potter sequence

Patterns of multiple malformations that occurstogether constitute syndromes

Recognition of syndromes is important to answer the questions that parents of all babies with congenital malformations ask namely.

What is it ?Why did it happen ?What does in mean for the child‘s future ?Will in happen again ?

Disorders caused by a defect in a singlegene follow patterns of inheritance described by

Mendel

Autosomal dominant disordersaffect both males and females and often be traced through many generations of a family. Affected people are heterozygous for the abnormal allele and transmit the gene for the disease to half of their offspring, whether male or female.

The incidence is 7/1000The age of onset of a disorder may be variableThe severity of many dominant conditions also variesconsiderably among affected members within family

Other characteristic features of AD inheritance

New mutations may account for the presence of dominant disorder in a subject who does not have a family history of the disease. When a disorderarises by new mutation the risk of recurrence infuture pregnancies for next pregnancy is negligible.

Homozygosity for dominant genes is uncommon, but may happened with certain conditions, such achondroplasia : 25% homozygous affected (lethal).50% heterozygous affected, 25% homozygous normal

Examples of autosomal dominant disorders

AchondroplasiaPolycystic kidney diseaseTuberous sclerosisNeurofibromatosisHuntington‘s choreaMarfan syndromeHereditary breast cancerFamilial adenomatous polyposisFamilial hypercholesterolemiaColonic adenocarcinoma

About 3 000 AD disorders are known (McKusick catalog)

Polycystic kidney disease – adult type the mutant gene PKD1 a PKD2

This common autosomal dominant trait affects1/1000 population

Results in cysts in the kidneys, liver, pancreas and spleen. The renal cysts are usually asymptomatic, renalfailure or hypertension ensues in the fourth decade.Offspring of affected person can be screened with ultrasound and 95% of gene carriers will be positiveby 20 years of age.

Achondroplasiadue to mutation of the fibroblast growth receptor 3 gene (FGFR3 gen)

Clinical findings

Short stature, prenatal onsetShort limbsMacrocephalyDepressed/flat nasal bridgeMid –face hypoplasiaRhizomelia of upper limbsTrident hand

Children with achondroplasia

Huntington‘s disease

Trinucleotide repeat expansions (CAG) more than 35 repeatsAge dependent penetrancy - disorders occuring

between the ages 35- 55Anticipations

One of the most devasting genetic disorders

Psychiatric symptoms – progressive chorea and dementiaatrophy of the small neurones in the putamen

and caudate atrophy of the large neurones in the globus pallidus

Progressive disability: death occurs on average 17 yearsfrom onset

Ethical problems with predictive testing

Marfan syndrome-The main defect of the connective tissues due to mutation of

the fibrillin 1 gene

General featuresCraniofacial: dolichocephaly, prognathismus, cleft palate, long narrow dental arch, high palateal vaultSkeletal: anterior chest deformity, dolichostenomelia

arachnodactylyscoliosistall stature

Ocular : ectopia lentis, flat cornea, myopia

Cardiovascular: dilatation of ascending aortamitral valve prolapse

Pulmonary: spontaneous pneumothorax

Apert syndrome

Tuberous sclerosis

AD inheritance, frequency 1 in 10 000 50-80% new mutations

Diagnosis: white skin patches facial fibroangiomatous rash (adenomasebaceum) skin fibromatous plaques (shagreen patches)enamal pitsintracranial calcification or periventricular hamartomamental retardation, epilepsyrenal angiomyolipomatacardiac rhabdomyomata

Variable expresivity

Probands with typical signs of tuberous sclerosis

Neurofibromatosis type I(von Recklinghausen disease)

Mutation of the tumor supresor gene on 17q11.2Frequency 1:3 000

Diagnostic criteriaPresence of café au lait patchesCutaneous neurofibromasLeisch nodules in the irisMalignant tumors (mainly nerofibrosarcomas or embryonal tumors) occur in 5% affected people

Neurofibromatosis type II - locus on chromosomes 22(central neurofibromatosis)

Diagnosis: bilateral acoustic neuromas (schwannomas)spinal tumours, intracranial meningiomas café au lait patches

Neurofibromatosis type I

Osteogenesis imperfecta, type I

Diagnosis: brittle bones with recurrent fractures, blue sclerae,condutive deafness due to otosclerosis dentinogenesis imperfecta, growth retardation

Autosomal recessive disorders

Both healthy parents carry the same recessive gene

The risk of recurrence for future offspring of suchparentes is 25%

Although the defective gene may be passed fromgeneration to generation, the disorder generally onlyappears within a single sibship – within one group

of brother and sisters.

Consanquinity increases the risk of AR disease because both parents are more likely to carry the

same defective gene

Examples of autosomal recessive disorders

Cystic fibrosisCongenital adrenal hyperplasiaDeafness (some forms)PhenylketonuriaFriedreich´s ataxiaSickle cell diseaseMicrocephaly (some forms)Many complex malformation syndromesGalactosemia Many inborn errors of metabolism

Cystic fibrosis

AR trait due to mutations in the cystic fibrosistransmembrane conductance regulator gene (CFTR)

locus at 7q31Incidence 1 in 2000 in northern Europe with carrierfrequency of 1 in 22, less common in Blacks in USA andOrientals

Commonest mutation (70%) is delta F508 (a 3bp deletion which removes a phenylalanine residue at position 508)

Diagnosis: sodium exceeds 60mmol/l and chlorides 70mmo/l

Clinical features: pancreatic insufficiency, chronic lungdisease due to reccurent infection, rectal prolapse, meconium Ileus, cirrhosis of the liver

Congenital adrenal hyperplasia

AR trait due to deletion, conversion or point mutation of the active cytochrome P450 gene involve in steroid 21 –hydroxylation, which are linked to the HLA haplotype

on chromosome 6Deficiency of 21 –hydroxylase is the commonest cause

Rarer deficiencies are known, which have differentclinical features and biochemical abnormalities

Diagnosis: neonatal vomiting, shock and death in the salt-losing form. Virilization of the female with ambiguous genitalia. Precocity in male. Elevated urinary ketosteroids and pregnantriol. Markedly elevated serum 17-hydroxyprogesterone and ACTH. Normal lifespan health and fertility due to replacement therapy.

Osteogenesis imperfecta congenita type II.- lethal

Diagnosis: brittle bones, multiple fractures at birth perinatatal lethalhydrocephalushydrops

Examples of X-linked recessive disorders

Duchenne muscular dystrophyBecker´s muscular dystrophyHaemophilia A and BMental retardation with of without fragile site Mukopolysacharidosis type IIBruton´s agamaglobulinemiaColor blindness

Examples of X-linked dominant disordersIncontinentia pigmentiRickets resistant to vitamin D Orofaciodigital syndrome

Duchenne (DMD) and Becker´s muscular dystrophyare allelic with mutation in the structural gene for protein

dystrophin at Xp21Molecular pathology reveals partial deletions, duplicationsand point mutations. 30% are new mutations

DMD incidence 1/3 000 male BMD incidence 1/20 000male

Diagnosis: onset in eary childhood of progressive proximalmuscle weakness. Calf pseudohypertrophywalking delayed.Elevation of CK, abnormal EMGchairbound in mild-childhood, death about 25years

BMD muclular dystrophy – often chairbound about 25 yearsfrom onset, lifespan may be normal

Congenital hydrocephalus X-linked recessive

Vitamin D resistant rickets

Diagnosis: growth retardation,reduced serum phosphate, treatable with large doses of vit.D or its activemetabolite calcitrol

Mitochondrial disorders

Mitochondria have their own DNA consisting of a doublestranded circulare molecule.

The mitochondrial genome encodes 22 type of transferand ribosomal RNA molecules that are involved in mitochondrial protein synthesis as well as 13 of thepolypeptides involved in respiratory chain system.As the main function of mitochondria is the synthesis of ATP by oxidative phosphorylation, mitochondrial disorders are most likely to affect tissues as the brain,skeletal muscle, cardiac muscle .

Disorders due to mitochondrial mutations often apper to besporadic. When they are inherited, they demonstratematernal transmission.

Examples of diseases caused by mitochondrial DNA mutations

Leber´s optic atrophy acute visual loss, otherneurological symptomes

MERF myoclonic epilepsyother neurological sympt.ragged red fibres in skelet.muscle

MELAS encephalomyopathylactic acidosisstroke like episodes

Genetic counselling dilemmas in mitochondrialdisease

Many disorders caused by mitochondrial mutation are sporadic

Severity is very variable and difficult to predict

It is difficult to advise asymtptomatic relatives who carry the mitochondrial mutation

It is not known wheather the degree of heteroplasmy inmother deternines risk to offspring

Common misconceptions about heredity

1. Absence of other affected family members means thatdisorder is not genetic

2. Any condition present at birth must be inherited

3. Genetic disease are untreatable

4. If only males or females are affected in the family this indicates sex linkage

5. 1 in 4 risk means that the next three children will be unaffected