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 genetic causes at least one third of all malformations. Nearly one –half stillbirth and 20% of early neonatal deaths are atrributable to major congenital malformations. Genetic disease now causes about one-half of all death in chilldhood and accounts for one-third of all pediatric hospital admissions Chronic diseases with significant genetic component affect 10-20% of the adult population
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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
Pře
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.
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
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
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: 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