Card Set Information
genetic disease swisshelm
genetic disease, swisshelmWhat is
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)
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....
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?
small mouth, oral cavity -> tongue thrusting
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?
What is the risk for Down Syndrome child with mother being 30, 35, 40 yrs. old?
What are the prenatal cytogenetic tests?
1. chorionic villus sampling
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?
Another cause for Down Syndrome besides nondisjuction is what?
what is Robersonian translocation
centric fusion of 2 acrocentric chromosomes
If Robertsonian translocation is balanced, what happened?
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
hypoplasia and hypocalcification
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?
Velo-cardio-facial syndrome (VCF)
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?
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%)
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?
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?
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.
: 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?
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
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
mutations of more than 1 gene cause the SAME DISORDER
mutations in same gene cause DIFFERENT disorders
de novo (new) mutation?
no family history
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
What are the dental anomalies for Van der Woude syndrome?
cleft lip w/ or w/o palate
lower lip pits
hypodontia or missing lateral or central incisor
What is the genetics for Van der Woude syndrome?
mutations in IRF6 in 70% of cases
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
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?
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?
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.
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?
sunken nasal bridge
unusually thick lips
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
benign focal malformation that resembles neoplasm in the tissue of origing
What is Cowden syndrome?
multiple hamartoma syndrome
gingival and palatal lesions; cobbestone appearance
thickening or furrowing of tongue
multiple skin tags
How is Cowden syndrome inherited? age related penetrance? Increased risk for what kind of cancer? Gene mutation?
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?
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 has what kind of lesions?
soft tissue skin tumors