-
What is the genome?
- total DNA content of a cell
- makes up the entire genetic information available to the organism
- encodes all the info for cellg rowth, division, and responsiveness to environment
- organized in to 23 linear double stranded DNA molecules
- somatic cells have 2 copies of each chromosome
- 30,000 - 40,000 genes
-
What is clinical cytogenetics?
cell genome at metaphase constitutional karyotype
-
What are some of the abnormalities of chromosome?
number and structure
-
What are the number abnormalities of chromosome?
- aneusomy (abnormal # of chromosome)
- monosomy
- trisomy
-
what are the structure abnormalities of chromosome?
- translocations and their derivatives
- deletions, duplications, rings
- inversions and their recombinants
-
Abnormalities can fall into 2 categories:
-
Mutations as a cause of disease - likely to be disease causing if what?
- does not occur in the normal population
- alters the protein function of expression
- segregates with disease in a given family and is absent in unaffected family members
-
what are the etiologies of genetic disease?
- 1. chromosomal - genomic imbalances
- 2. multifactorial - genes + environment
- 3. single gene disorders - autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant
-
What are the indications for constitutional cytogenetic studies (8)?
- *cytogenetic studies are performed to diagnose and understand genetic diseases, including cancer
- documentation of a cytogenetic syndrome
- multiple congenital abnormalities w/o a known etiology
- developmental delay and minor anomalies
- rare diseases with unusual presentation
- family history of the above
- history of a familial chromosomal abnormality
- intrauterine growth retardation or failure to thrive w/o a known etiology
- history of spontaneous abortions
-
Trisomy 21 is also known as....
Down Syndrome
-
What is the most common chromosomal abnormality in live born individuals?
Trisomy 21 - Down Syndrome
-
What is the most common cause of cognitive disability?
Trisomy 21 - DOwn Syndrome
-
What are the characteristic phenotype of Trisomy 21/ Down Syndrome?
- short stature
- microcephaly
- small mouth, oral cavity -> tongue thrusting
- epicanthic folds
- cardiac anomaly
-
What is the seen with trisomy and maternal age?
- positive correlation with incidence of trisomies 21, 18, and 13 with advanced maternal age
- older than 35 yrs. old
-
Where in the cell cycle does Trisomy 21/Down Syndrome happen?
amternal meiosis I nondisjunction
-
Genetic counseling is offered for who?
- for advanced maternal age
- 35 y.o women
-
What is the risk for autosoma trisomies and AMA for Trisomy 21, 18, 13?
- Trisomy 21: 1/650
- Trisomy 18: 1/8000
- Trisomy 13: 1/20,000
-
What is the risk for Down Syndrome child with mother being 30, 35, 40 yrs. old?
- age 30: 1%
- age 35: 2.8%
- age 40: 10.4%
-
What are the prenatal cytogenetic tests?
- 1. chorionic villus sampling
- 2. amniocentesis
-
For chorionic villus sampling, when is it performed? risk for miscarriage?
- performed at 10-12 wks gestation
- cultured cells from extraembryonic chorionic mesoderm in 5-7 days
- rapid results early in gestation
- procedure -related risk for miscarriage = 1%
-
for amniocentesis, when is it performed? risk of miscarriage? and others?
- when - 15-18 wks gestation
- amniotic fluid contains true embryonic fetal cells
- in situ cell culture: 5-10 days
- procedure-related risk for miscarriage = 0.5%
-
what % of Trisomy 21 are familial?
3%
-
Another cause for Down Syndrome besides nondisjuction is what?
Robertsonian translocation
-
what is Robersonian translocation
centric fusion of 2 acrocentric chromosomes
-
If Robertsonian translocation is balanced, what happened?
no phenotype
-
What happens when Robertsonian translocation is not balanced?
risk to have offspring with unbalanced karyotypes: 46 chromosomes, 3 copies of chromosome 21 -> Down Syndrome
-
With Down Syndrome, what are the oral anomalies?
- Palate with v-shaped high vault
- angle of the mouth pulled down (result of hypotonic musculature)
- small oral cavity - protruding tongue creates speech and articulation problems
-
For Down Syndrome, what are the dental anomalies?
- 30-50% have microdontia - affects primary and secondary dentition
- supernumery teeth
- abnormal spacing
- crown variants
- hypoplasia and hypocalcification
- delayed eruption
- increased risk of periodontal disease
-
Loss of a portion of a chromosome is caused by what 3 things?
- loss of DNA segment
- loss of contiguous genes
- monosomy for these genes
-
What are the names of the syndrome cause by 22q11 deletion?
- DiGeorge syndrome
- Velo-cardio-facial syndrome (VCF)
- Opitz syndrome
- Conotruncal anaomlay face syndrome
-
Infant with cardiac anomaly of term baby with uneventful pregnancy history, cleft lip and palate, hypocalcemia, ventricular septal defect, and absent thymus will have what deletion?
22q11
-
What happened in and is the characteristics of DiGeorge, Velocardiofacial, Shprintzen Syndromes?
- disturbances of migration of neural crest cells into pharyngeal arches and pouches
- thymic aplasia, hypoplasia -> T cell immune dysfunction
- parathyroid hypoplasia -> hypocalcemia
- midline defects -> clefts, conotruncal heart defects
-
What is the variability in the phenotype of DiGeorge/Velocardiofacial Syndrome?
- cleft palate - almost always
- cardiac disease - frequent
- typical faces (often, subtle)
- learning disabilities - frequent
-
What is spectrum of findings for 22q11 Deletion Syndrome?
- cardiac abnormalities (74%)
- palatal anomalies (69%) - cleft palate, submucosal cleft...
- facial features - long,narrow face, beaked nose
- learning disabilities (70%)
- immunodeficiency (77%)
- other features, feeding problems, renal, hypocalcemia, hearing loss
-
For DiGeorge, Velocardiofacial, Shprintzen Syndrome, how is their phenotype? What do they have in common? Sporadic or familial? How to test for it?
- phenotypic spectrum
- share same mutation - 3Mb deletion w/in 22q11
- most sporadic, 10% familial
- FISH testing of family members
-
Newest technology of Microarray. Describe what it does.
- Like thousands of FISH experiment
- detection of small mutations - DNA sequence gains and losses
- microdeletion syndrome detection
- Polymorphic DNA sequence gains and losses
- Patient DNA combine with control DNA. normal = yellow. red=loss. green = gain
- target DNA on slide is single stranded oligomers
- can be done with 5 different patients of same sex
- limited ability to detect mosaicism
-
what are the advantages of chromosomal microarray.
- Detects chromosomal gains and losses
- 1 array = 180,000 FISH studies
- detects abnormalities in known "hot spots"
- can be use to characterize chromosome abnormalities detected by karyotyping
- genome-wide arrays may also detect abnormalities in "backbone" of genome
-
What are the limitations of CMA?
- cannot detect balanced rerrangments
- cannot detect specific genetic/ DNA mutations, single base pair changes
- detectin of copy number variants (CNVs) may have unclear clinical significance
- may not detect low-level mosaicism
-
What is the cause of monogenic, Mendelian disorders?
single gene defects
-
When is monogenic, Mendelian disorders expressed? what is the incidence? Can it be inherited?
- usually expressed in childhood
- incidence, about 0.36% in liveborn population
- 1-3% of children have some congenital malformation - half involve oral/facial
- heritable genetic disorders
-
In automsomal dominant inheritance of single gene disorders, what characteristic do you see in family? What percentage that child will receive it? Need how many allele to cause phenotype?
- phenotype expressed in every generation
- 50% risk of inheriting trait of affected parent
- mutation in 1 allele causes phenotype
-
Hungtingon disease is an example of what type ?
autosomal dominant gene mutations
-
Cause of Hungtington disease?
mutation in Huntington gene - amplification of trinucleotide repeat (CAG)
-
Huntington disease causes what?
adult onset neurodegenterative disorder
-
Incidence of Huntington disease.
1/10,000 indiv of European origin
-
How to confirm Huntington Disease?
through DNA testing for CAG repeat size
-
What are several of other autosomal dominant gene mutations other than Huntington's disease?
- Familial Hypodontia
- Mesiodens
- Amelogenesis imperfecta, hypocalcified type
-
What is familial hypodontia?
mild reduction of number of teeth
-
What is mesiodens?
supernumberary tooth, between max central incisors
-
What is amelogenesis imperfecta, hypocalcified type?
- normal quantity of enamel but soft
- improper differentiation of emaloblasts -> brown color
- 70% of AI is this form
- prevalence 1/14,000 live births
-
Describe autosomal recessive.
- rare diseases: expression of phenotype requires 2 alleles
- carriers have one normal allele with no phenotype
- recurrence risk for each sibling of proband is 1 in 4
- phenotype observed among siblings of the proband, not parents, offspring, or other relatives
-
What are some examples of autosomal recessive disorders?
- cystic fibrosis - abnormal ion transport protein
- sickle cell anemia - abnormal hemoglobin
- Phenylketonuria (PKU) - enzyme deficiency
-
What are the characteristic of autosomal recessive disease Ellis van Creveld syndrome?
- postaxial polydactyly
- short stature, shortening of forearms and lower legs
- congenital heart malformations
- dysplastic nails and teeth
- caused by mutations in EVC gene, chromosome 4, p16 responsible for phenotype
-
Describe X-linked diseases.
- mutation of genes on X chromosome
- phenotypic expression generally in males
- all daughters of affected males carry his X chromosome
- sons of carrier females are at 50% risk for inheritance of mutated gene
-
Example of X-linked disease.
- amelogenesis imperfecta, X-lined hypoplastic type
- in males, thin smooth enamel
- in females, enamel with vertical furrows
-
what is lyonization?
random X inactivation in females
-
What is the Lyon hypothesis?
- Single active X chromosome in mammals
- functionally hemizygous
- mechanism for dosage compensation
- random inactivation of maternal or paternal X chromosome early in female embryogenesis
- Fidelity of X(matern) or X(patern) inactivation in clonal descendents
- skewing of X inactiviation for tissue specificicity
-
Genetic heterogeneity?
mutations of more than 1 gene cause the SAME DISORDER
-
clinical heterogeneity?
mutations in same gene cause DIFFERENT disorders
-
de novo (new) mutation?
no family history
-
variable expresssivity?
trait is expressed differently among individuals carrying same mutatnt gene, even win a family
-
What is the sex ration for cleft lip with or w/o cleft palate? results from what? heterogeneity?
- sex ration - 2 Males 1 Females
- CL/P results from failure of lip closure w/ secondary failure of palate closure
- genetic heterogeneity - mixture of genese and environmental factors
-
For cleft lip, what is the percentages of isolated cases, familial, and syndromic forms?
- isolated cases - 75-80% (multifactorial)
- familial, single gene forms (10-15%)
- syndromic forms (1-5%)
-
What is the most common single-gene cleft syndrome? mode of inheritance?
- Van der Woude syndrome
- autosomal dominant
-
What are the dental anomalies for Van der Woude syndrome?
- cleft lip w/ or w/o palate
- cleft uvula
- lower lip pits
- hypodontia or missing lateral or central incisor
-
What is the genetics for Van der Woude syndrome?
- autosomal dominant
- mutations in IRF6 in 70% of cases
- clinical heterogeneity
-
what is holoprosencephaly (HPE)?
- developing forebrain fails to divide into 2 separate hemispheres/ventricles
- with about 80% have associated craniofacial anomalies
- genetic heterogeneity = 25-50% numberical/structural chromosome anomaly
- 18-25% recognizable syndrome
-
How is nonsyndromic HPE inherited? expressions?
- inherited in autosomal dominant manner
- extreme variability of phenotype
- mild expression - microcephaly, singl central incissor, hyptelorismm midfacial hypoplasia, cleft lip
-
Nonsyndromic HPE mutations where?
in more than 4 genes account for 40-50% of HPE
-
AI heterogeniety?
clinical and genetic heterogeniety
-
AI causes what?
- defect of dental enamel formation
- teeth are small, discolored, grooved or pitted, and prone to rapid wear and breakage
-
What are the 4 main types of AI?
- hypoplastic
- hypomaturation
- hypocalcified
- hypomaturation/hypoplasia/taurodontism
-
What is osteogenesis imperfecta (OI)?
- group of genetic disorders due to improper formation of type I collagen
- range from lethal(Type II) to mild (type I)
-
wut is the clinical features of OI?
- multiple fractures
- short stature
- hearing loss
- blue sclera
- dentinogenesis imperfecta
-
what is the caracteristic tooth crown color for dentinogenesis imperfecta (DI)?
- blue gray or yellow brown and translucent
- caused by defective, abnormally colored dentin shining thru the overlying enamel
- underlying defective dentin not able to adequately support the unaffected enamel
- often flakes off
-
There are 2 types of Dentinogenesis imperfecta. what is it?
- Type I - associated with osteogenesis imperfecta
- Type II - most common. no increased frequencey of bone fractures
-
Inheritance for OI/DI.
autosomal dominant
-
What is ectodermal dysplasia?
- primary defect in development of 2 or more tissues derived from ectodermal layer (hair, skin, nails, teeth)
- more than 2190 hundred clinically distinc syndromes - ectodermal dysplasia type I (ED1) most common
-
What is Christ-Siemens-Touraine syndrome? Inherited as? caused by?
- Ectodermal dysplasia I
- inherited as X-linked recessive
- caused by mutation in ectodysplasin A gene
-
Characteristic of ED1 Christ-Siemens-Touraine syndrome?
- prominent forehead
- sunken nasal bridge
- unusually thick lips
- large chin
- eye abnormalities, decreased tearing
-
ED1 in skin.
- partial of complete absense of certain sweat glands
- soft thin and dry skin
- skin peeling/scaling and eczema
-
ED1 with nails.
spoon shaped nails
-
ED1 with hair.
- fine, brittle and scant hair (hypothrichosis)
- absent or scanty eyelashes and eyebrows
-
ED1 in teeth.
- malformation of certain teeth: conical or pegged teeth, hypodontia or complete anodontia, delayed eruption of permanent teeth
- jaw radiographs indicated for infants w/ fever of unknown origin and family history of EDs
-
hamartoma?
benign focal malformation that resembles neoplasm in the tissue of origing
-
What is Cowden syndrome?
- multiple hamartoma syndrome
- clinical features:
- gingival and palatal lesions; cobbestone appearance
- thickening or furrowing of tongue
- facial tricheilemmonas
- multiple skin tags
- subcutaneous lipomas
-
How is Cowden syndrome inherited? age related penetrance? Increased risk for what kind of cancer? Gene mutation?
- autosomal dominant
- age related penetrance
- PTEN gene mutation
- increase risk for cancer - breast, thyroid, endometrial
-
How is familial adenomatous polyposis inherited? mutation in what? % of de novo germline mutations?
- autosomal dominant
- mutations in APC tumor suppressor gene
- 30% de novo germline mutations
-
Clinical features of FAP?
- hundred to thousands of adenomas by early adulthood
- untreated polyposis -> 100% risk of colorectal cancer
- risk of extracolonic tumors
-
A variant of FAP is what syndrome?
Gardner's syndrome
-
Gardner's syndrome has what kind of lesions?
- extraintestinal:
- desmoid tumors
- osteomas
- supernumery teeth
- soft tissue skin tumors
|
|
