Statue of Liberty


Autosomal Dominant=50% if one effected, 75% if both get one gene


Clinical Features


Molecular Biology

Dx/ Tx

1. Achondroplasia

Most frequent form of short limb dwarfism

Penetrance – Complete

Late paternal age

Dwarfism with long narrow trunk and short extremities.

Large head, normal intelligence, redundant skin folds, cervical sp cord compression

4p16.3. Encodes fibroblast growth factor receptor –3 (FGFR-3)

D/T: Single base mutation

Most cases d/t new mutation in spermato - genesis. Gene dosage effect- homozygotes more severe, with early death.

Mutated transmembrane domain on FGFR3. Binding of FGF to heparan sulfate of syndecan on cell surface does not occur.

Dominant negative effect

Dx: Prenatal diagosis aims to exclude homozygosity

2. Neurofibromatosis
(von Recklinghausen disease)

Expressivity - variable

Penetrance - absolute

Late paternal age

Cafe -au-lait spots, > two neurofibromas (fibromatous skin tumor); More than two Lisch nodules (iris tumors)


17q11.2 (NF1 gene). Encodes neurofibromin protein

D/T: Numerous types of Mutations of the NF1 gene d/t large size of the gene

Neurofibromin -  acts as a tumor suppressor protein. Tumors from NF patients display a loss of both copies of neurofibromin gene.

Dx: Linkage markers (indirect DNA diagnosis)


3. Retinoblastoma (RB)  

Embryonic neoplasm. Sperms carrying mutated RB1 gene have fertilization advantages.

Penetrance - Incomplete


Often bilateral benign (retinoma) or malignant (frank retinoblastoma)

Retinal mass protruding into the vitreous with “cottage cheese calcification; trilateral RB (pineal gland)

13q14.1-14.2  (RB1 gene). Encodes retinoblastoma protein.

 D/T: deficient Rb protein.

Two Hit hypothesis occurs with Loss of hetergygosity

Rb inhibits transcription and progression from G1 to S phase Rb rescues p53 anti-oncogene from degradation, hence is a tumor suppressor.


4. Huntington disease (HD)
The mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years.


Chorea movement

Impairment of voluntary motor functions


psychiatric disturbances

Explosiveness, apathy Psychosis. If from father, sx more severe d/t imprinting.


4p16. Encodes Huntingtin. D/T: Growing CAG trinucleotide repeat mutation. The expressivity in heterozygotes and homozygotes is similar (no gene dosage). Shows


Abnormal huntingtin may be insoluble and precipitate.

Toxicity to neurons rather than the lack of function.



5. Marfan syndrome (MS) is a heritable disorder of fibrous connective tissues

MS - classic example of pleiotropy

Penetrance - complete

Expressivity - variable

Increased height, long limbs and digits.

Aneurysm of the aorta, aortic dissection (leads to mortality).

Arachnodactily - «wrist sign»; Subluxation (displacement) of the lenses.

15q.21 (fibrillin-1 gene (FBN1)). Encodes fibrillin. D/T: Abnormal fibrillin has a dominant-negative effect, that is it disrupts normal architecture of the connective tissues, particularly of elastin fibers

A mutation in fibrillin gene results in deficit of synthesis, secretion or incorporation of the elastin molecule into the extracellular matrix.


Dx: Since each MS family carries a unique mutation, diagnosis is made by linkage markers

Tx: Symptomatic

6. Osteogenesis imperfecta

Generalized connective tissue disorder

Penetrance - incomplete

Expressivity – variable


Multiple bone fractures usually resulting from minimal trauma

Blue sclerae throughout life; Hearing loss leading to profound deafness

Thin, easy bruised skin


17q21-q22 (collagen 1a gene). Encodes collagen 1D/T: Reduced amounts of normal collagen I; abnormal collagen that is less stable. Different mutations in collagen 1a gene cause different clinical variants

Osteogenesis imperfecta congenital (neonatal lethal form) - d/t new mutation in collagen 1a gene.  Considered dominant.  Disruption of Gly-X-Y patterns.

Dx: By ultra  -sonography or/and X-ray; Skin fibroblasts secrete less collagen, have abnl. shape and grows slowly in vitro (Dx value).

7. Ehler-Danlos syndrome

Penetrance - incomplete

Expressivity - variable


Skin is thin, translucent striking bruisability

Joints hyperextensible (“India rubber man” shows).  Acrogeric hands and face

Dissecting arterial aneurisms. Pregnancy -rupture of bowel, uterus

2q31 (collagen 3a gene). Encodes collagen IIIa.

D/T: single amino acid substitution (Gly to X)

mutated collagen IIIa chain disrupt tertiary structure of collagen helix.


The mutated collagen is unstable at 37oC and is degraded. However, it is stable at lower temperatures and can be included into extracellular matrix (hence, acrogeric hands and face).

Dx: Immuno-histochemistry: Low levels of collagen III in connective tissues (skin). Genetic tests: linkage analysis.

8. Familial hypercholesterolemia (FH)

Probably the most frequent mendelian disorder: the incidence is ~1 in 500.

Penetrance - absolute

Expressivity - variable


Xanthomas - deposition of cholesterol in tendons and skin.

Premature atherosclerosis and MI at the age of 30.

Arcus senilis in patients under 50.


19p13. Encodes LDL receptor.

D/T:  2-3> levels of plasma cholesterol from birth.

Gene dosage effect - Homozygotes have 5-6 fold elevations

Abnormally high levels of low density lipoproteins (LDL).

Mutations seen in FH patients impair the function of the LDL receptor in various ways:

Synthesis, Transport, Binding of LDL, Clustering in pits, Recycling


Dx: prenatal Dx in homozygotes

Heter. - direct molecular DNA testing, linkage markers

Tx: Diet, cholestyramine, lovastatin

Tx not effective in homozygotes.

Autosomal Recessive=25% need 2 hom genes-Skips Generations


Clinical Features


Molecular Biology

Dx/ Tx

1. Tay Sach

Progressive neuro-degenerative disorder;

Lysosomal storage disease; 1 in 3600 Ashkenazi Jews

Infantile – early onset mental and physical retardation, paralysis.

Cherry-red spots.

Late onset- age 20-30.


15q23-q24. Encodes hexosaminidase A (HEXA) a subunit.

D/T: Ashkenazi Jews – 4bp insertion; French Canadians - large deletion in exon 1

Lack of HEXA, cells cannot degrade ganglioside in their lysosomes and GM2 are accumulated.

Mainly in neurons.


Dx: CVS or amniotic fld

Tx: None


2. Xeroderma Pigmentosum

Disease of high sensitivity to sunlight

Freckle like lesions in exposed areas occur in the first year of life and leads to skin cancer.

9q22.3 (XP correcting gene). Encodes a protein that binds to DNA

D/T: deletions

DNA repairing machinery can not be recruited to the site of DNA damage.


Dx: DNA sequencing


3. Adenosine deaminase deficiency

One of the severe combined immuno-deficiency (SCID)

Recurrent respiratory infection, course is progressive and pt dies d/t chronic infection, T cells most sensitive

20q13.11. Encodes ADA. Involved in catabolism of adenosine

D/T: Absence of ADA.

In the absence of ADA, adenosine and dATP accumulates above toxic levels (purine pathway).


Dx: Enzyme activity in CVS, AF

Tx: Bone marrow transplantation. PEG-ADA weekly.

4. Pituitary Dwarfism

Some forms are AD


Short stature with normal body proportions and normal fertility.

Face appear younger, skin of adults shows progeria


17q22-q24 (PD gene). Encodes growth hormone.

D/T: large deletions

Consanguinity common


GH is released from anterior pituitary, GH binds to GHR in liver and induce IGF-1 which induce cell growth and proliferation.

Dx: measurement of GH in response to stimulation by GHRH. Tx: recombinant human GH

5. Cystic Fibrosis

Most common fatal genetic disease in Caucasians; Selective advantage – resistance to cholera and Salmonella.

Sweat – salty (increased conc of Na ions).

Infertility – female d/t highly viscous cervical mucus, males – absence of vas deferens (see molecular)

7q31. Encodes CFTR (cystic fibrosis trans-membrane conductance regulator = chloride ion transporter/channel)

D/T: deletion of phenyl-alanine at 508 (DF508)

Pulmonary – COPD d/t thick secretion and recurrent infection; Pancreatic insufficiency – obstruction of exocrine pancreatic ducts; Liver dz – biliary tract obstruction.

Dx: linkage anal., CVS, AF;

Tx: pancreatic enzyme, symptomatic.

6. Phenylketouria

Selective advantage – protect against toxins of Aspergillus, toxin cause spontaneous abortions

Mental retardation evident by 6 months, “mousy odor

Thin, easy bruised skin;

Maternal PKU – teratogenic effect of Phe cross placenta

12q24.1. Encodes PAH. D/T: single base substitution

Many pt are compound heterozygotes

Homozygotes are deficient in phenylalanine hydroxylase (PAH) which converts Phe to Tyr.

Dx: Ferric chloride urine test

Molecular DNA test

Tx: Phe- free diet

7. Sickle Cell Anemia

Hypochromic anemia

Infection- major cause of death (fibrotic spleen and chronic stimulation of bone marrow leads to immune deficiency)

Heterozygotes – Normal unless at high altitude

Severe hemolytic anemia (Under low O2 tension, abnormal shaped RBC), Hb range from 6-10mg/dL, jaundice and gallstones, impaired mental function.  Chronic hemolysis leads to bone marrow hyperplasia (bossing of skull).

Position 6 in b gene. D/T: Point mutation/ single base substitution (A to T), Glu to Val at position 6 in b gene. HbS binds normally to O2 (Expression of each globin chain is regulated by promoter sequences and LCR – locus control region)

In deoxygenated form, b globin becomes sticky, form rod shaped polymers, then ppt in RBC.

Sickle cells are less flexible and easily clump, occluding capillaries (sickle cell crisis).


Dx: HbA and HbS can be readily distinguished by electrophoresis.


8. a - Thalassemias

Thalassemias – most common human single gene disease


Affects both fetal and adult Hb (both intrauterine and postnatal disease)

Hemolytic anemia - In absence of a globin chain, chains from b globin cluster forms a mono-tetramers (g 4 =Hb Bart’s, b4= HbH).

In a thalassemia with HbH, gradual ppt resulting in inclusion bodies (Heinz bodies)

a globin gene.

D/T: a chain synthesis is reduced or absent deletions of a globin gene (two identical a globin gene on Chr 16 with highly homologous areas around them). Facilitates unequal crossing over.


Excess b chain is produced, the chain ppt in the cell, damages the membrane and leads to hemolytic anemia. The severity depends on the number of  a globin chain lost (eg. Carrier = 3 a genes, anemia =1, hydrops fetalis = 0)

Dx: Prenatal

Tx: Repetitive Blood transfusion and iron chelators

Survival into adult unusual.


9. b - Thalassemias

Only expressed in postnatal period


Hemolytic anemia (Hb<5g/lL), jaundice, hepato/ splenomegaly, Thalassemic facies (prominent cheek bones and protruded upper jaw), skull bossing

D/T: Single base substitution. Abnormalities in RNA splicing (Use of alternative site or use new splicing junctions on a competitive basis)

Thalassemia major- compound heterozygotes in homozygotes

Thal. minor – hetero- zygotes with hypochromic RBC and slight anemia

See above

10. Hereditary persistence of HbF

Fetal Hb (HbF) = a2g2

In fetal liver

Adult Hb (HbA) = a2b2


Heterozygote that carry sickle cell mutation or thalassemia are resistant to Plasmodium vivax, malaria 

D/T: Large deletion in the b globin cluster on Chr 11. Result in a complete loss of both d and b globin.

HbF compensate (100%) for the absence of HbA.

Heterozygotes of these mutations have RBC that are less hospitable for the Plasmodium.


X -  Linked Diseases

I. X -  Linked Recessive-Males need 1X, females 2X's, No male to male, skip generations, 1/2 son affected 1/2 female carriers


Clinical Features


Molecular Biology

Dx/ Tx

1. Duchenne Muscular Dystrophy

Males are genetic lethals


Progressive muscle weakness starting at 1-2 yrs, pseudohypertrophy of calf muscles, by age 12, in wheelchair. Die of cardiac/resp failure

Xp21. Encodes dystrophin (expressed in muscle cells)

Largest gene known

D/T:  Deletion

1/3 cases-new mutation

Dystrophin connects actin filaments to the membrane of muscle cells, mutated ones causes muscle cell to collapse

Dx: DNA tests

Linkage markers

Carriers – serum creatine kinase

2. Fragle X Syndrome

Inherited mental retardation; (Second only to Down’s)


Mental retardation – varies

Dysmorphic facial features (large ears, long face with large mandible)


Fragile site

Can be seen in medium lacking folic acid.

Xq27.3  Encodes FMR1 (fragile site mental retardation).

D/T: Extensive length of CGG repeats (>200).  Disease worsens when passed on by a carrier female.

Low penetrance – “carrier male” = fragile x with no phenotype. Anticipation especially if passed on by a female

Gene expressed mostly in brain and testes. Extensive length of CGG repeats blocks gene expression resulting in a decreased amount of FMR1 protein. 

Dx: DNA test

Cytogenic test

Immuno-staining of hair root

Tx: None

3. Hemophilia A

Bleeding disorder caused by a deficiency in coagulation factor VIII.

Mutation rate is higher in males than in females d/t crossing over of X and Y.

Hemorrhages into muscle, joints, and skin. The severity of bleeding is inversely related to residual VIII amounts. Affected females: d/t Turner’s, nonrandom X inactivation, consaguinal, uniparental disomy.

Xq28. Encodes Factor VIII.

D/T: Severe phenotype – inversion and large deletions; Milder phenotype – point mutation. Homozygous female more severely affected than male hemizygous.

Coagulation cascade- Factor VIII is part of intrinsic coagulation pathway, It polymerizes with VW factor to form Factor VIII complex.

Dx: DNA based/ linkage markers

Tx: Infusion of human/ recombinant factor VIII

4. Ichthyosis

Excessive scale formation on scalp, ears, neck,

Impaired barrier function.

Disease onset at birth.

Xp22. Encodes steroid sulfatase (STS).

D/T: Extensive deletion in STS gene.

Intra-chromosomal recombination.

Function of STS is to remove sulfate residues from cholesterol sulfate

With this deficiency, undegraded cholesterol sulfate accumulates.

Dx: Prenatal DNA tests

Tx: Symptomatic

5. Glucose-6-phosphate dehydrogenase deficiency

400 mil people in the world – some resistance to malaria

Anemia – When RBC encounters an oxidant, the SH group of the globin chains become oxidized. This causes denaturing of Hb and they ppt as Heinz bodies.

Xq28. Encodes G6P.

D/T: single base substitution

Critical: in bacterial infection, drugs (antimalaria), fava beans (generates oxidants).

G6P enzyme in pentose phophate pathway.  The oxidized G6P results in NADPH which donates H to glutathione. Glutathione  protect cell from oxidative injury.


6. Color Blindness


Abnormal perception of color

X-linked – Red and Green pigments

AR – Blue cone on chr 7

Normal color vision- trichromatic

Dichromacy - Defect in cone opsin gene

Monochromatic – Two or more abnormal

Encodes cone opsins.

D/T: deletions of a cone opsin gene d/t unequal crossing over

Protanopia- loss of red

Deuteranopia- loss of green

Opsins- pigment which transform the energy of the light into the chemical signals.



II. X-Linked Dominant-twice often females, no male to male, multi-gen, males-all daughters, female-50% m vs female

1. Vitamin D Resistant Rickets

Abnormal bone mineralization with clinical features similar to vitamin D deficiency, however not responding to vitamin D tx.

Severe growth retardation weakness of bone, bowing of legs, frontal bossing,

Severity higher in males than in females

Xp22. Encodes PHEX (phosphate endopeptidase X). Function unknown.

Phosphate can not be reabsorbed in the kidney tubules, Lab: Hypo-phosphatemia (mobilizes phosphate from the bones),

Normal serum calcium

Tx: Kidney transplant not effective; Oral phosphate in combination with calcitriol. GH help increase height and phosphate reabsorption.

2. Congenital generalized hypertrichosis


More abundant hair which covers excessive areas of skin, no hormonal abnormalities.

Not identified.



Mitochondrial Inheritance and Atypical Inheritance Mode

Mitochondrial Inheritance-Only femle to female, all offspring of affect females affected, no offspring of male affected


Clinical Features


Molecular Biology

Dx/ Tx

1. Male-limited precocious puberty

Inheritance- Autosomal dominant sex-limited phenotype. Therefore,  AD disease that the phenotype is only expressed in males.


Precocious development of the external genitalia, early muscle bulk, early growth spurt with early epiphyseal fusion. Normal fertility.

2p21. Encodes luteinizing hormone receptor.

D/T:  Asp to Gly substitution. 

LCGR in males is expressed on Leydig cells (secrete testosterone). Constitutive stimulation of LCGR results in hyperplasia and hyperfunction of Leydig cells and very high testosterone level (testotoxicosis).


2. Leber hereditary optic neuropathy

Inheritance- Mitochondrial. Therefore, maternal inheritance only. Both males and females are affected, but affected males do not transmit the phenotype.

Manifests in midlife with painless loss of central vision. The disease progress within 4 months resulting in complete loss of light perception in severe cases. Ancillary sx include defects in cardiac conduction, seizures.

Various positions in the Mitochondria DNA.

D/T: single base substitutions in mtDNA.

Heteroplasmy = Expressivity very variable, depending on the proportion of defective (mutations presents in some mitochondria but one in others in the same cell).

Causes improper functioning of the electron transportation chain.

Dx: Opthal-mological finding- microangiopathy of retina, disk edema.

3. Myoclonic epilepsy with ragged red fibers (MERF)

Inheritance- Mitochondrial.

Epilepsy with dementia and ataxia associated with muscle weakness.

MtDNA. Encodes leucin tRNA. D/T: Single base substitution in mtDNA. 

Mitochondria in MERF are abnormally shaped and contain protein inclusion.


4. Uniparental disomy

(Not a disease)


Uniparental disomy – both homologous chromosomes from one of the parents are transmitted to the offspring.

Example #1. Hemophilia A transmitted from father to son.

Example #2. Cystic fibrosis transferred from a carrier mother to daughter.

Maternal or paternal genes may be selectively inactivated. When both maternal or paternal chromosomes are inherited, the gene may be inactive without any mutation.


5. Prader-  Willi Syndrome

Inheritance- Autosomal dominant


Obesity, muscular hypotonia, short stature, mental retardation, small hands and feet, hypogonadism, rarely live >30 yrs d/t cardiac failure.

15q11-q13.  Encodes SNRPN (small nuclear ribonuclear protein N).

D/T: Major cause- loss of segment on paternal chromosome 15 (80%), 20% d/t uniparental disomy.

SNRPN is involved in mRNA processing. The absence of paternal copy is responsible for the phenotype, maternal copy is inactivated by DNA methylation. If the paternal gene is deleted,  the defect can not be compensated.


6. Angelman syndrome

Inheritance- Autosomal dominant. Majority of cases are sporadic.


Severe mental and motor retardation

Ataxia with wide-based gait and puppet-like movement, epilepsy, absence of speech, happy disposition with bursts of laughter.


15q11-q13.  UBE3A gene. Encodes ubiquitin-protein ligase E3A.

D/T: Loss of segment on maternal chr.


In the brain, the gene is expressed only on the maternal chr. If UBE3A is deleted, paternal chr cannot compensate d/t inactivation of the gene.



7.  MELAS:  Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes Mitochondrial    

For the Medical Students of America edited by Scott D. Neff, DC DABCO MPS-BT CFE DABFE FFABS FFAAJTS and courtesy of the American Academy For Justice Through Science  


© & TM 1998 American Academy for Justice Through Science. All rights reserved.

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