Genetic Disorders

Genomics•Study of all genes in the genome and their

interactions•Two most common DNA variations

▫Single-nucleotide polymorphisms▫Copy number variations

EpigeneticsHeritable changes in gene expression

that are not caused by alterations in DNA sequence

Classification

•Disorders related to mutations in single genes with large effects (Mendelian disorders)

•Chromosomal disorders

•Complex multigenic disorders

Mutations• Permanent change in the DNA• Interfers with protein synthesis at various levels

• Point mutation▫ Within coding sequences▫ Within noncoding sequences

• Frameshift mutation▫ Deletions▫ Insertions

• Trinucleotide-repeat mutations▫ Amplifications, dynamic

Mendelian Disorders•Autosomal dominant

•Autosomal recessive

•X-linked

Autosomal Dominant•Manifested in the heterozygous state•Some proportion due to a new mutation•Incomplete penetrance•Variable expressivity•Influence of environmental factors•Age of onset delayed in many conditions•Most are loss-of-function mutations•Table 5-1 common disorders

Autosomal Recessive• Largest category of mendelian disorders• Trait does not usually affect the parents• Siblings have a ¼ chance of having the trait• Think about consanguinity if mutant gene is rare• Expression of the defect tends to be more

uniform• Complete penetrance is common• Onset is frequently early in life• New mutations are rarely detected clinically• Many of the mutated genes encode enzymes• Table 5-2 common disorders

X-linked Disorders•Most are recessive•Few X-linked dominant ( e.g. vitamin D-

resistant rickets)•Affected male does not transmit the

disorder to his sons, but all daughters are carriers

•The heterozygous female usually does not express the full phenotypic change because of the paired normal allele

•Table 5-3 common disorders

Biochemical and Molecular Basis of Mendelian Disorders• Enzyme defects and their consequences

▫Accumulation of substrate▫Decreased amount of end product▫Failure to inactivate a tissue-damaging substrate

• Defects in membrane receptors and transport systems

• Alterations in the structure, function, or quantity of nonenzyme proteins

• Mutations resulting in unusual reactions to drugs

Disorders associated with Defects in Structural Proteins•Marfan syndrome

▫Disorder of connective tissues▫Defect in fibrillin-1▫Skeletal abnormalities▫Ocular changes▫Cardiovascular lesions – life-threatening

•Ehlers-Danlos syndromes▫Defect in the synthesis or structure of

fibrillar collagen

Disorders associated with Defects in Receptor Proteins•Familial hypercholesterolemia•Mutation in the gene encoding the

receptor for LDL, which is involved in the transport and metabolism of cholesterol

Disorders associated with Defects in Enzymes• Lysosomal Storage diseases

▫Tay-Sachs▫Niemann-Pick DiseaseType A,B,C▫Gaucher disease▫Mucopolysaccharidoses

• Gycogen storage diseases▫Hepatic forms▫Myopathic forms▫Miscellaneous forms

• Alkaptonuria

Disorders associated with Defects in Proteins that Regulate Cell Growth•Proto-oncogenes•Tumor-suppressor genes•Important in the pathogenesis of tumors

Complex Multigenic Disorders•Polymorphism•Common disease/common variant

hypothesis•Environmental factors•Difficult to distinguish from mendelian

disease at times

Chromosomal Disorders• Normal karotype

▫ G banding▫ Terminology

• Structural abnormalities▫ Aneuploidy

Nondisjunction Anaphase lag

▫ Mosaicism▫ Deletion

Ring chromosome▫ Inversion▫ Isochromosome▫ Translocation

Balanced reciprocal Robertsonian

Cytogenic Disorders involving Autosomes•Trisomy 21 (Down syndrome)•Trisomy 18 (Edwards syndrome)•Trisomy 13 (Patau syndrome•Chromosome 22q11.2 Deletion syndrome

Trisomy 21•1/700 incidence in US•Maternal age•Flat facial profile, oblique palpebral fissures,

epicanthic folds, intellectual disability,hypotonia

•40% congenital heart disease•Increased risk of leukemia•Abnormal immune responses•Alzheimer disease after 40 years of age•Figure 5-21 clinical features of trisomies

Chromosome 22q11.2 Deletion Syndrome• DiGeorge syndrome

▫Thymic dysplasia immunodeficiency▫Parathyroid hypoplasia hypocalcemia▫Cardiac malformations▫Facial anomalies

• Velocardiofacial syndrome▫Facial dysmorphism▫Cleft palate▫CVS anomalies▫Learning disabilities

Cytogenic Disorders involving Sex Chromosomes•Lyon hypothesis•Klinefelter syndrome•Turner syndrome•Hermaphroditism•Pseudohermaphroditism

Lyon Hypothesis•Only one of the X chromosomes is

genetically active•The other is rendered inactive at random at

about day 16 of embryonic life•Inactivation of the same X persists in all

cells derived from each precursor cell•Barr body•Not all of the genes on the inative X are

switched off•Both Xs are required for normal oogenesis

Klinefelter Syndrome•Male hypogonadism•Two or more X and one or more Y•Elongated body, gynecomastia•Reduced spermatogenesis and male

infertility•Increased risk of breast cancer,

extragonadal germ cell tumors, autoimmune disorders

•Longest CAG repeat X chromosome remains active

Turner Syndrome•Complete or partial monosomy of the X

chromosome•Hypogonadism in phenotypic females•Single most important cause of primary

amenorrhea•Figure 5-23 Clinical features

Hermaphroditism and Pseudohermaphroditism•Genetic sex•Gonadal sex•Ductal sex•Phenotypic or genital sex•True hermaphrodite – presence of both ovarian

and testicular tissue•Pseudohermaphrodite – disagreement between

phenotypic and gonadal sex▫Female – excess androgen▫Male – complete androgen insensitivity syndrome

Single-Gene Disorders with Nonclassic Inheritance•Diseases caused by trinucleotide-repeat

mutations•Disorders caused by mutation in

mitochondrial genes•Diseases associated with genomic

imprinting

•Diseases associated with gonadal mosaicism

Fragile X Syndrome• Prototype of mutation with long repeating sequence

of three nucleotides• Second most common genetic cause of intellectual

disability after Down syndrome• Macro-orchidism• Normal carrier males• Affected females –much higher than in other x-linked

recessive disorders• Risk of phenotypic effects depends upon position in

pedigree• Anticipation – worsens with each successive

generation

Leber Hereditary Optic Neuropathy•Prototype of mitochondrial inheritance

disorder•Maternal inheritance •mtDNA complement of the zygote is

derived entirely from the ovum•Genes incode for enzymes involved in

oxidative phosphorylation•Threshold effect•Neurodegenerative disease – progressive

loss of central vision

Genomic Imprinting• Imprinting selectively inactivates either the maternal or

the paternal allele• Uniparental disomy• Angelman

▫ Deletion of maternally-derived chromosome 15▫ “Happy puppet” – intellectual disability, ataxia,

inappropriate laughter, seizures

• Prader-Willi▫ Deletion of paternally-derived chromosome 15▫ Intellectual disability, hypogonadism, hypotonia,

hyperphagia, short stature, obesity, small hands and feet

Molecular Diagnosis of Genetic Diseases• Indications for analysis of germ line genetic

alterations• Indications for analysis of acquired genetic

alterations• PCR and detection of DNA sequence alterations• Polymorphic markers and molecular diagnosis• Molecular analysis of genomic alterations

▫ Southern blot▫ FISH▫ Array CGH

• Epigenetic alterations – do not alter the DNA sequence• RNA analysis- RNA viruses – HIV, HCV

Indications for Germline Alterations• Prenatal genetic analysis

▫Amniocentesis, chorionic villus sample, or umbilical cord blood

▫Mother of advanced age▫Parent who is a carrier of a translocation or

inversion▫Parent with a previous child with a chromosomal

abnormality▫Fetus with ultrasound-detected abnormalities▫Parent who is a carrier of an X-linked disorder▫Abnormal levels of triple markers (AFP. BetaHCG,

estriol)

Indications for Germline Alterations• Postnatal genetic analysis• Peripheral blood lymphocytes• Multiple genetic anomalies• Unexplained intellectual disability and/or

developmental delay• Suspected aneuploidy• Suspected unbalanced autosome• Suspected sex chromosome abnormality• Suspected fragile-X• Infertility• Multiple spontaneous abortions

Indications for Acquired Alterations•Diagnosis and management of cancer

▫Detection of tumor-specific alterations▫Determination of clonality▫Identification of specific alterations that

can direct treatment▫Determination of treatment efficacy▫Determination of Gleevec-resistant forms of

tumors

Indications for Acquired Alterations•Diagnosis and management of infectious

diseases▫Detection of microorganism-specific

genetic material for diagnosis▫Identification of alterations that are

associated with drug resistance▫Determination of treatment efficacy