Pathogenesis: Autosomal Dominant -mutation to FGFR3 gene, gain of function -> stops bone growth -80% de novo (all paternal)

Symptoms: short bones, hyptonia, prominent forehead, & compressed spinal cord

Inheritance: AD, fully penetrant, homozygosity is lethal. 1 in 15,000 to 1 in 40,000 live births

Pathogenesis: Autosomal Recessive -mutation in CFTR gene-regulates ion channels, affects many mucus secreting organs, 20% mechonium illeus in new borns

Symptoms: chronic respiratory problems, poor growth, 95% males azoospermic. syx appear in childhood, tissue specific expression of mutation, depending on location of mutation

Inheritance: AR 1 in 3200 N. European, 1 in 313 Hutterites, Alberta

Symptoms: 2/3 have congitive and motor impairment(chorea), 1/3 have psychiatric problems, avg. onset 35-44 can present in childhood. Severe atrophy of neostriatum. Variable expresivity, reduced penetrance (preexpansions), sex-specific anticipation-paternal premutations expand in offspring

Pathogenesis: Mutation in HD gene, codes for huntingtin-unknown function. >36 CAG repeats is mutant

Inheritance: AD, 97% inherit a mutant from affected parent.   80% of early onset is from father.  in W. Europeans 3-7 per 10,000. Japanese 0.1-0.38 per 100,000

Symptoms: Multisystem disorder, inludes ocular (ectopia lentis), cardiovascular (enlarged aorta, mitral valve) and skeletal (tall like Lincoln), dural, pulmonary and skin. Syx develop with age. epigenetic/environmental factors play role in determining phenotype

Pathogenesis: Autosomal Dominant, mutation to FBN1-codes for fibrilin, effects microfibril formation which normally bind to and reduce growth factors. dominant negative pathogenesis= mutant fibrillin inhibit normal microfibril formation or stimulate proteolysis of them.  25-35% de novo mutations

Inheritance: AD, 50%.  1 in 10,000

Symptoms: short stature, ovarian dysgenesis, cardiac (50% w/ bicuspid aortic valve), hearing problems, webbed neck, broad chest,  edema,

Pathogenesis: Chromosomal disorder, Female Monosomy X -absence of a second X chromosome. 70-80% from sperm w/o sex chromosome.  Less often, loss of X from zygote -results in 45,X mosaicism. Haploinsufficiency -1 or more X-linked genes not inactivated

Inheritance: 50% 45,X. 25% 45,X mosaicism. 25% structural abnormality on 2nd X.  Not related to maternal age. Sporadic, so risk of recurrence not above normal. 1 in 2000 to 1 in 5000 liveborn girls

Symptoms: Facial/head abnormalities, behavioral problems, macroorchidism.  MR -moderatein males; mild in females.  Severity of phenotype depends on repeat length mosaicism and repeat methylation

Pathogenesis: X-linked Dominant, mutation in FMR1 gene which codes for FMRP - expressed in many cells, mostly neurons, chaperone mRNA to translation machinery. 99% from triplet repeat expansion, CGG.

Inheritance: Nearly all male and 40-50% females (variable X Inactivation) with full mutation have FXS.  Empirically, risk for a premutation carrier is 50% male offspring, 25% female -depends on size of premutation. Genetic anticipation in females w/ premutation. somatic mosaicism. Haplotype effect.  Female- 16-25 per 100,000, male- 8-13 per 100,000

Symptoms: Degenerative.  Muscle degeneration and weakness, cardiac compromise, IQ< 1 SD, syx present 3-5yrs, avg age at death 18yrs.  Phenotypic variability from X Inactivation. tested for elevated creatine kinase

Pathogenesis:  Mutation in DMD gene -codes for dystrophin, found in muscles and brain neurons, confers stability to sarcolema.  60-65% large deletions (mostly oogenesis), 5-10% duplications, 25-30% small deletions,insertions,nucleotide changes (mostly in sperm).

Inheritance: X-linked recessive. Skewing of X Inactivation leads to variable expressivity, most carrier females still have cardiac problems. 1/3 of mothers with 1 DMD son are not carriers.

Symptoms: 2 types -HA (VIII) and HB(IX). coagulation problems, mostly affects males, severity predicted by level of factor VIII or IX activity.

Pathogenesis: mutation to factor VIII or IX gene, leads to deficiency or dysfunction of clotting factor factor VIII or IX. Inversions are most common 25% HA, and 40-50% severe HA.  HB -many mutations, none more common.  Factor IX Leyden-unusual varient from pt. mutation, causes severe HB in childhood but spontaneous resolution in puberty.

Inheritance: X-linked recessive.  Carrier mother has 50% chance to pass to daughter, but daughter has low risk of hempophilia (low levels of skewing of X-inactivation)  50% risk of H for sons. 98% mothers of son with pt. mutation or inversion, recieved gene from de novo mutation in their fathers sperm (affected male's m. grandfather). deletions usually in female meiosis.  HA -1 in 5,000 to 10,000.  HB -1 in 100,000