I.                    Aneuploidy (chromosomal syndromes)

    A. Trisomy 21 = Down’s Syndrome

                                                              i.      Maternal age effect

                                                           ii.      95% à trisomy of chromosome 21 (75% nondisjunction in 1^st                                                                            meiotic division)

                                                         iii.      4% à unbalanced translocation

                                                          iv.      1% à mosaic karyotype

                                                             v.      phenotype:  hypotonia, round flat face, upslanting palpebral                                                                    fissures, small simplified ears, short neck 

B.      Trisomy 18 = Edwards Syndrome

                                                              i.      Maternal age effect

                                                           ii.      95% spontaneously aborted

                                                         iii.      mostly à trisomy  (rarely unbalanced translocation)

                                                          iv.      multiple congenital abnormalities & severe internal                                                                                   malformations:  micrognathia, dolichocephaly, overlapping fingers,                                                                    rocker- bottom feet, severe growth retardation, unilateral cleft lip,                                                                    heart defect, elfin facies

                                                             v.      90% die w/i 1^st year

C.     Trisomy 13 = Patau Syndrome

                                                              i.      Maternal age effect

                                                           ii.      80% à trisomy

                                                         iii.      20% à unbalanced translocation

                                                          iv.      most spontaneously aborted

                                                             v.      rarely live past few months

                                                          vi.      severe congenital malformations:  bilateral cleft lip & palate,                                                                    microphthalmia, hexadactyly, heart defect, cutis aplasia, neural tube                                                                    defects

II.                 Sex chromosome abnormalities

A.      Turner syndrome (45X)

                                                              i.      No maternal age effect

                                                           ii.      >99% spontaneously aborted

                                                         iii.      70-80% à paternal X missing

                                                          iv.      55% à 45X

                                                             v.      45% à other (ring chrom., isochrom., marker chrom., deletion,                                                                    mosaicism

                                                          vi.      some mosaics à risk devo. gonadal tumors

                                                        vii.      short 4^th metacarpal, sometimes puffy hand & feet

B.      Kleinfelter syndrome (47XXY)

                                                              i.      testicular atrophy

                                                           ii.      sterile

                                                         iii.      psychosocial problems

C.     47XYY Syndrome

                                                              i.      males with normal phenotype (tall, normal intelligence & fertility)

                                                           ii.      increased risk behavioral problems

D.     Trisomy X syndrome (47 XXX)

                                                              i.      phenotypically normal

                                                           ii.      learning problems

III.               Autosomal deletions (single gene syndromes)

A.      Prader-Willi syndrome (deletion 15q12,or 15q11.2-15q13)

                                                              i.      Paternal imprinting à 70% have deletion, 30% have maternal                                                                    uniparental disomy

                                                           ii.      Candidate gene = small nuclear ribonucleoprotein associated                                                                    peptide (SNRPN)

                                                         iii.      1/10,000

                                                          iv.      severe neonatal hypotonia & feeding problems, apneic spells,                                                                    males are hypogonadal, by age 3 à hyperphagia & obesity, mental                                                                    retardation is variable, short stature, narrow bifrontal diameter, small                                                                    hands & feet

B.      Angelman syndrome = Happy puppet syndrome (deletion 15q12, or 15q11.3-15q13)

                                                              i.      Maternal imprinting à 70% deletion, 3-5% paternal uniparental                                                                    disomy, 8% abnormal chrom. 14 imprinting process, 20% gene                                                                    mutations

                                                           ii.      Candidate gene = E6-associated-protein (E6-AP) ubiquitin-                                                                   protein ligase (UBE3A)

                                                         iii.      Rare

                                                          iv.      Sever mental retardation, seizures, ataxic gait, severe motor                                                                    delay, absence of speech, paroxysms of laughter, distinctive facial                                                                    appearance

IV.               Autosomal dominant

A.      Achondroplasia

                                                              i.      high new mutation rate

                                                           ii.      paternal age effect (>37)

                                                         iii.      gain of function (more receptors are made, but they are                                                                    dysfunctional)

                                                          iv.      dysplasia

B.      Huntington

                                                              i.      low mutation rate

                                                           ii.      variable time of onset

                                                         iii.      triplet repeat

                                                          iv.      founder effect

                                                             v.      detect mutation via Southern blotting

C.     Marfan Syndrome fibrillin mutation

                                                              i.      Paternal age effect

                                                           ii.      Pleiotropy

                                                         iii.      Long fingers, aortic root dilatation, lax joints, “can die on                                                                       basketball courts”

D.     Osteogenesis Imperfecta

                                                              i.      gonadal mosaicism frequent

                                                           ii.      pleiotropy (genes having more than one effect on physiology or                                                                    anatomy)

                                                         iii.      locus heterogeneity

                                                          iv.      Type 1:  mild, blue sclera, brittle bones, presenile deafness

a.        AD

b.        Collagen is normal, but Qty of collagen cut in ½

c.        Null alleles

                                                             v.      Type 2:  perinatal lethal, severe skeletal abnormalities, dark                                                                    sclera

a.        AD (new mutation)

b.        Abnormal collagen I due to substitution of Gly  @ COOH terminal

c.        Missense mutation

                                                          vi.      Type 3:  progressive deforming fractures often @  birth, limited                                                                    growth, blue sclera

a.        AD

b.        Gly substitutions @ NH₂ terminal

c.        Missense mutation

                                                        vii.      Type 4:  normal sclera, deforming mild to moderate, short,                                                                    hearing loss

a.        AD 

b.        Gly substitution @ NH₂ terminal

c.        Missense mutation

E.      Ehlers Danlos Syndrome Type VII

                                                              i.      Congenital hip dislocation, joint hypermobility, soft skin                                                                    w/ abnormal scarring

                                                           ii.      Deletion of exons from COL1A1 & COL 1A2 genes encoding                                                                    the amino-terminal conversion sites (AD)

                                                         iii.      Defect in enzyme that cleaves at the amino-teminal site (AR)

F.      Familial Hypercholesterolemia

                                                              i.      co-dominant due to mutation @ LDL receptor

                                                           ii.      heterozygous (cholesterol = 300-400 mg.dl)

                                                         iii.      homozygous (chol. >700 mg.dl)

                                                          iv.      class 1: receptor synthesis disruption

                                                             v.      class 2: receptor transport (ERà golgi) disrupted

                                                          vi.      class 3: LDL binding by receptor disrupted

                                                        vii.      class 4:  receptor clustering in coated pit disrupted

G.     Polycystic Kidney Disease

                                                              i.      variable time of onset

                                                           ii.      locus heterogeneity (same phenotype by mutations @ distinct                                                                    loci)

H.     Myotonic Dystrophy

                                                              i.      variable time of onset

                                                           ii.      anticipation

                                                         iii.      triplet repeat

                                                          iv.      detect mutation via Southern blotting

I.        Hemochromatosis

                                                              i.      gender influences increase variation in expression

J.      Spinal muscle atrophy

                                                              i.      triplet repeat

V.                  Autosomal Recessive

A.      Xeroderma pigmentosum

                                                              i.      consanguinity (25% from 1^st cousin marriages)

                                                           ii.      Chromosome instability syndrome

                                                         iii.      pronounced cutaneous photosensitivity

                                                          iv.      increased risk for basal & squamous cell carcinoma                                                                                    multiple genes id’d involved w/ nucleotide excision repair

B.      Sickle cell anemia

                                                              i.      allele heterogeneity (diff. mutations @ same locus)

                                                           ii.      use ASO (allele specific oligonucleotides which specifically                                                                    hybridize to mutant & wild type sequences) to directly detect the                                                                    mutation

                                                         iii.      also use Southern blot in DNA diagnosis (detect lost restriction                                                                    enzyme site)

                                                          iv.      all cases caused by 1 mutation = missense mutation in                                                                    beta-globin gene @ codon 6

                                                             v.      newborn screening

                                                          vi.      African-american population

C.     Cystic Fibrosis

                                                              i.      use ASO’s to directly detect the mutation

                                                           ii.      majority of cases (2/3) due to 3-base pair deletion ->                                                                    lose phenylalanine, with remaining 1/3 due to many different mutations

                                                         iii.      1/25 carrier frequency

D.     Phenylketonuria

                                                              i.      Hyperphenylalanemia

                                                           ii.      mutation (different) in phenylalanine hydroxylase à                                                                                       no phenylalanine to tyrosine conversion à phenylalanine                                                                    accumulation à toxic to brain!!

                                                         iii.      four alleles account for defects in Caucasians (most common is                                                                    defect in exon 12 donor splice siteà skipping of 12th exon in RNA                                                                    splicing à premature translational stop)

                                                          iv.      mental retardation, seizures, decreased skin pigmentation,                                                                    microcephaly, congenital heart disease, intrauterine growth retardation

                                                             v.      sometimes due to defect in DHPR/BH4 à affects multiple                                                                    systems

                                                          vi.      treatment:  dietary reduction phenylalanine

                                                        vii.      newborn screening

                                                     viii.      diffusible substrate leads to effects in multiple sites

E.      Mucopolysaccharidoses (GAGs)= Lysosomal storage diseases

                                                              i.      hydrolase defect -> accumulation of substrate in lysosome à                                                                    cell death in organ where substrate produced

                                                           ii.      organomegaly

                                                         iii.      clinically & genetically heterogeneous

                                                          iv.      phenotypic homology

                                                             v.      Hurler syndrome

a.        alpha-L-iduronidase defect:  dermatan sulfate, heparan sulfate

b.        @ 6-8 months

c.        corneal clouding, dysostosis multiplex, hepatosplenomegaly, coarse facies, stiff joints, mental retardation, death < 10 years

                                                          vi.      Schie syndrome

a.        alpha-L-iduronidase defect

b.        after 5 years

c.        normal intelligence & life span, corneal clouding, stiff joints, valvular heart disease

                                                        vii.      Hurler/Schie syndrome

a.        alpha-L-iduronidase defect

b.        intermediate phenotype between Hurler & Schie

                                                     viii.      Sanfilippo A (most severe of Sanfilippo)

a.        Heparan N-sulfatase defect

b.        Btw 2-6 years

c.        Hyperactivity & retardation, progressive neurodegeneration, mild somatic features,hirsutism, sleep disorders, long life à vegetative

                                                          ix.      Sanfilippo B

a.        alpha-N-acetylglucosaminidase defect

b.        similar symptoms to Sanfilippo A

F.      GM2 Gangliosidoses = Lysosomal storage diseases

                                                              i.      No effective treatments!!

                                                           ii.      Loss multiple enzyme activities

                                                         iii.      Phenotypic homology

                                                          iv.      Tay Sachs

a.        founder effect or heterozygote advantage (3 alleles account for 99% of mutations)

b.        1:100,000

c.        a gene affected à alpha subunit defective à  no Hexosaminidase A isoenzyme

d.        higher in Ashkenazi Jews

e.        CNS problems:  motor weakness begins @ 3-5 months, increased startle, hypotonia, poor head control, decreased attentiveness, rapid deterioration after 10-12 months, cherry red spot!

                                                             v.      Sandhoff disease

a.        1:300,000

b.        B gene affected à beta subunit affected à no Hexosaminidase A & no Hexosaminidase B

c.        Similar symptoms to Tay Sachs, but sometimes with organomegaly & boney involvement

                                                          vi.      GM2 activator deficiency

a.        rare

b.        activator gene affected à activator protein deficiency à lots of Hex A & Hex B, but can’t assemble

c.        similar symptoms to Tay Sachs

G.     Beta thalassemia

                                                              i.      allele heterogeneity

                                                           ii.      use haplotyping in prenatal diagnosis

                                                         iii.      Sardinian population

                 H.  Glycogen Storage Diseases

VI.               X-linked Recessive

A.      Fragile X (X-linked mental retardation)

                                                              i.      Anticipation

                                                           ii.      Detect mutation via Southern blotting

B.      Lesch-Nyhan Syndrome

                                                              i.      HPRTase deficiency

                                                           ii.      Skewed inactivation

                                                         iii.      Defect in purine metabolism à no hypoxanthine guanine                                                                                   phosphoribosyltransferase à lose ability to reuse hypoxanthine                                                                    & guanine to make IMP & GMP

                                                          iv.      Variety of of clinical phenotypes exist

a.        0% activity à severe:  choreoathetosis, spasticity, variable MR, uric acid overproduction -> nephropathy -> growth & mental retardation, self-mutilation, aggressiveness)

b.        1-30% activity à gout

                                                             v.      diagnosis:  urine screening to find uric acid to creatinine                                                                    ratio (>2.0 suspicious), HPRT enzyme levels in RBCs

                                                          vi.      treatment:  allopurinol decreases serum uric acid levels,                                                                    NO effective therapy for neurologic complications

                                                        vii.      phenotypic homology

C.     Duchenne’s Muscular Dystrophy

                                                              i.      Haldane’s rule applies

                                                           ii.      Direct detection of a deletion or major gene rearrangement (2/3                                                                    of cases have detectable mutation)

                                                         iii.      DNA diagnosis via PCR analysis or Southern blotting

                                                          iv.      Skeletal muscle weakness & progressive degeneration, cardiac                                                                    involvement, mental retardation (30% of males), pseudohypertrophy                                                                    of calf muscles

D.     Becker’s Muscular Dystrophy

                                                              i.      Haldane’s rule applies

E.      Hemophilia

                                                              i.      No Haldane’s because male gamete mutation rate is higher                                                                    than in female gametes à therefore the likelihood that the mother of an                                                                    affected male is a carrier is higher

F.      Ornithine Transcarbamylase deficiency

                                                              i.      direct detection of a deletion or major gene rearrangement

                                                           ii.      Southern blot used for DNA analysis

                                                         iii.      In mitochondria (urea cycle reaction)

                                                          iv.      Ammonium build-up à toxic to brain!!

                                                             v.      CNS problems:  Vomiting, lethargy, difficulty feeding, “sepsis”                                                                    picture

                                                          vi.      Diagnosis:  ammonium level & serum amino acid analysis

                                                        vii.      Treatment:  stop protein feeds!, dialysis or exchange transfusion

                                                     viii.      Female carriers can have stigmata

                                                          ix.      Late presenting males w/ OTCD

                                                             x.      Phenotypic homology:  different stigmata depend on level of                                                                    residual enzyme activity

G.     Mucopolysaccharidose (only X-linked one!!)

                                                              i.      Hunter syndrome

a.        iduronidate sulfatase defect

b.        similar symptoms to Hurler, but with slower progression, NO corneal clouding, & unique pebbly skin lesion

VII.             X-linked Dominant

A.      Hypophosphatemic rickets

                                                              i.      kidneys can’t absorb phosphate à abnormal ossification of                                                                    bones à bowed legs

                                                           ii.      new mutation can occur any time -> phenotype present in 1^{st                                                                   person in whom mutation present}

VIII.          Sex-limited inheritance = usually in one of sexes due to ANATOMIC or HORMONAL differences

A.      Male pattern baldness usually in males

B.      Congenital adrenal hypoplasia (21-hydroxylase deficiency)

                                                              i.      in females:  ambiguous genitalia due to virilization

                                                           ii.      in males:   Normal

                                                         iii.      newborn screening

IX.               Mitochondrial inheritance

A.      Kearns-Sayre syndrome

B.      Laber’s hereditary optic atrophy

C.     Mitochondrial encephalopathy

D.     Myodromus epilepsy

X.                 Multifactorial inheritance

A.      Cleft lip/palate

                                                              i.      malformation

                                                           ii.      most common isolated anomaly

                                                         iii.      Pierre-Robin sequence

B.      Clubfoot

                                                              i.      deformation

                                                           ii.      Potter sequence

                                                         iii.      Neural tube defect

C.     Congenital heart defect

D.     Neural tube defects (spina bifida, anencephaly)

                                                              i.      ameliorate with folate during pregnancy

                                                           ii.      malformation

                                                         iii.      MSAFP screening in pregnant women <35 years

E.      Dislocated hip

F.      Coronary artery disease

                                                              i.      more common in males

G.     Congenital dislocation of hip

                                                              i.      more common in females

                                                           ii.      deformation

                                                         iii.      Ehlers Danlos also

H.     Hypertension

                                                              i.      ameliorate by not smoking

XI.               Cancers

A.  Wilms tumor

                                                              i.      paternal imprint of tumor suppressor alleles à two hit hypothesis

B.      Osteosarcoma

         i.     paternal imprint of tumor suppressor alleles

C.     Retinoblastoma

                                                              i.      paternal imprint of tumor suppressor allele RB1

                                                           ii.      germline mutation or somatic mutation

                                                         iii.      AD inheritance pattern (not AD phenotype manifestation!!) w/ 90% penetrance

                                                          iv.      Bilateral, unilateral, or multifocal

                                                             v.      Tumor of retinoblasts early in life

                                                          vi.      45% of offspring of parents w/ a RB germline mutation will                                                                    be affected -> also increased risk of osteosarcoma

                                                        vii.      screen via ophthalmologic exams for newborns & children

D.     Embryonal rhabdomyosarcoma

                                                              i.      paternal imprint of tumor suppressor alleles

                                                           ii.      hereditary cancer

E.      Breast Cancer

                                                              i.      hereditary cancer

                                                           ii.      familial cancer

                                                         iii.      5-10% has AD inheritance pattern.  BRCA are tumor suppressor genes

                                                          iv.      BRCA1: 40%, breast & ovarian cancer

                                                             v.      BRCA2: 35%, male beast cancer

                                                          vi.      Lifetime risk of any female is 10-15%, while if have BRCA gene,                                                                    risk increases to 60-85% by age 80

                                                        vii.      Direct detection of BRCA1 or BRCA2 mutations via ASO

F.      Neurofibromatosis

                                                              i.      constitutional mutation

G.     Li-Fraumeni Cancer family

                                                              i.      AD inheritance

                                                           ii.      Rare

                                                         iii.      Germline mutation in p53 tumor suppressor gene (increases                                                                    when DNA damaged to incur apoptosis or G1 arrest for DNA repair)

                                                          iv.      Family has multiple types of cancers: soft tissue sarcomas,                                                                    early onset breast cancers, leukemia, brain tumors, adrenal cortical                                                                    tumors, etc.

H.     Burkitt lymphoma

                                                              i.      chromosome translocation

                                                           ii.      c-myc proto-oncogene moved next to promoter à over                                                                             transcribed

I.        Chronic myelogenous leukemia

                                                              i.      creation of new chimeric gene

                                                           ii.      c-abl & ber genes

J.      neuroblastoma

                                                              i.      gene amplification

K.      Hereditary non-polyposis colorectal carcinoma

                                                              i.      5-10% of colon cancer (usually on right side of colon)

                                                           ii.      AD inheritance & 70% penetrance

                                                         iii.      DNA repair gene mutations

                                                          iv.      Multiple family members affected

                                                             v.      Increased risk of cancers in abdominal area

L.      Fanconi anemia

                                                              i.      AR inheritance

                                                           ii.      Chromosome instability syndrome due to DNA repair defects

                                                         iii.      Progressive pancytopenia w/ childhood onset & predisposition                                                                    to leukemia & solid tumors

                                                          iv.      Hyperpigmentation, low birthweight, stunted growth, variable                                                                    skeletal malformations (radial ray defects), hypogonadism

                                                             v.      Screening:  chomosome breakage test

M.    Bloom syndrome

                                                              i.      Chromosome instability syndrome

                                                           ii.      telangiectatic erythema of face, photosensitivity, & stunted                                                                    growth

                                                         iii.      increased incidence of carcinomas & leukemias

                                                          iv.      hypersensitive to UV, ionizing radiation, & chemicals

                                                             v.      BLM gene on chrom. 15

N.     Ataxia telangiectasia

                                                              i.      Chromosome instability syndrome

                                                           ii.      progressive cerebellar ataxia, oculocutaneous telangiectasia,                                                                    & bronchopulmonary infections

                                                         iii.      increased incidence of leukemia

                                                          iv.      ATM gene on chrom. 11q

XII.            Contiguous gene deletion syndromes

A.      VCFS

                                                              i.      FISH analysis

                                                           ii.      Continuum to DiGeorge syndrome

                                                         iii.      Conal trunkal heart defect, long fingers, w/ age -> psychiatric                                                                    disturbances

                                                          iv.      CHARGE association

XIII.          Sequences

A.      Potter sequence = kidney dysplasia à decreased amniotic fluid à lung hypoplasia, facial compression, clubfeet

                                                              i.      lethal

                                                           ii.      limb position defects

B.      Pierre-Robin sequences = underdevo. Lower jaw à tongue prevents palatal fusion à cleft palate

C.     Neural tube defect = neural tube fails to close à interrupted spinal cord à club feet, hydrocephalus, neurogenic bladder, holoprosencephaly

 

Tags: achondroplasia, aneuploid, angelman syndrome, becker's muscular dystrophy, chromosome, cystic fibrosis, duchenne's muscular dystrophy, ehlers danlos syndrome type 7, familial hypercholesterolemia, fibrillin mutation, fragile x, happy puppet syndrome, hemochromatosis, hemophilia, hunter syndrome, huntington syndrome, hurler syndrome, hypophosphatemic rickets, kleinfelter syndrome, Lesch-Nyhan syndrome, lysosomal storage diseases, marfan's syndrome, mucopolysaccharidoses, myotonic dystrophy, ornithine transcarbamylase deficiency, osteogenesis imperfecta, phenylketonuria, polycystic kidney disease, prader willi, sandhoff disease, sanfilipo a, schie syndrome, sickle cell anemia, trisomy 13, trisomy 18, trisomy 21, trisomy x, turner syndrome, xeroderma pigmentosum

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