Card Set Information
Genetic Diseases Path
Genetic Diseases I & II - Path
At what stage is clinical cytogenetics captured?
Cell genome at metaphase
When is a mutation likely to be disease causing?
Does not occur in normal population
Alters the protein function or expression
Segregates with disease in a given family and is absent in unaffected family members
What are some indications for constitutional cytogenetic studies?
documentation of a cytogenetic syndrome
multiple congenital abnormalities without a known etiology
developmental delay and minor anomalies
rare diseases with unusual presentation
family history (including chromosomal abnormality)
intrauterine growth retardation or failure to thrive without a known etiology
history of spontaneous abortions
Which chromosomal abnormality is the most common abnormality in live born individuals and the most common cause of cognitive disability?
Trisomy 21 (maternal meiosis I nondisjunction)
What's a characteristic phenotype of Trisomy 21?
small mouth, oral cavity -> tongue thrusting
Which 3 trisomies are positively correlative with advanced maternal age?
21, 18, and 13
List and describe the two common prenatal cytogenetic tests.
Chorionic Villus Sampling
- performed at 10-12 wks
- cultured cells from extraembryonic chorionic mesoderm in 5-7 days
- rapid results early in gestation
- procedure risk for miscarriage
- performed at 15-18 wks
- amniotic fluid contains true embryonic (fetal) cells
- in situ cell culture
: 5-10 days
- procedure-related risk for miscarriage
Describe familial inheritance of Downs
3% of Trisomy 21 are familial
- Robertsonian translocation
: centric fusion of 2 acrocentric chromosomes (multiple copies in 1 of the meiotic products and absence of 21 in the other)
Balanced, so no phenotype
Risk to have offspring with unbalanced karyotypes
: 46 chromosomes, 3 copies of chrom 21 --> Downs
What are some oral anomalies of Downs?
Palate w v-shaped high vault
angle of mouth pulled down (hypotonic musculature)
small oral cavity (protruding tongue creates speech and articulation problems)
Name some dental anomalies of Downs
30-50% have microdontia
: affects primary and secondary dentition
- supernumerary teeth
- abnormal spacing
- crown variants
- hypoplasia and hypocalcification
- delayed eruption
Increased risk of periodontal disease
Describe a chromosomal structural abnormality: deletions
loss of a portion of a chromosome
- loss of DNA segment (usually many many genes!)
- loss of contiguous genes
- monosomy for these genes
What are some prime examples of a microdeletion? What type of genetic testing would you employ to diagnose this?
Conotruncal anomaly face syndrome
**USE FISH testing, as karyotypic wouldn't show the deletion
What's the cause/pathway for DiGeorge, Velocardiofacial, Shprintzen Syndromes? How does this manifest?
Disturbance of migration of neural crest cells into pharyngeal arches and pouches
Thymic aplasia, hypoplasia --> T-cell immune dysfunction
Parathyroid hypoplasis --> hypocalcemia
Midline defects --> clefts, conotruncal heart defects
What is the spectrum of findings of the 22q11 deletion syndrome?
: velopharyngeal incompetence (VPI), cleft palate, CL & CL/P, submucosal cleft, bifid uvula
: long, narrow face, beaked nose
: feeding problems, renal, hypocalcemia, hearing loss
What's the deletion that most have with DiGeorge, Velocardiofacial, Shprintzen Syndrome?
phenotypic spectrum of genetic disease
most have 3 Mb deletion within 22q11.21
a 480 kb critical region
- most sporadic, but about 10% are familial
Describe Microarray technology
comparative genomic hybridization
detection of SMALL mutations (DNA sequence gains and losses)
Microdeletion syndrome detection
"private" mutations of clinical significance
polymorphic DNA sequence gains and losses
** CMA is mix of 5 individuals of same sex --> works off ratios of patient DNA to same sex control. Loss
: ratio < 0.8, Gain: ratio > 1.2.
- target DNA on slide (chip) is single-stranded oligomer of 60 bases.
- aCGH detects gains and losses ONLY (NOT balanced rearrangements)
- LIMITED ability to detect mosaicism
List some advantages to CMA over FISH
- CMA detects chromosomal gains and losses, some of which may be submicroscopic. One array = 180,000 FISH studies
- detects abnormalities in known "hot spots" of genome
- genome-wide arrays may detect abnormalities in "backbone" of genome (ie
- can be used to characterize chromosome abnormalities detected by karyotyping (specific size of imbalance and genes involved)
List some limitations of CMA
- cannot detect balanced rearrangements
- cannot detect specific genetic/DNA mutations, single base pair changes, etc. (as in CF)
- may not detect low-level mosaicism
- detection of copy number variants (CNVs) may have unclear clinical significance
What are some characteristics of Monogenic, Mendelian Disorders?
single gene defects
usually expressed in childhood
: 0.36% in liveborn population
1-3% of children have congenital malformation
heritable genetic disorders
Describe Autosomal Dominant single gene disorder inheritance pattern
Phenotype expressed in every generation
child of affected parent has 50% risk of inheriting trait
mutation in ONE allele causes phenotype
Name some examples of autosomal dominant genetic disorders
: progressive neuronal degeneration
: muscle weakness & wasting
: vascular disease
: abnormal elastic tissue
: malignant tumor of eye
: abnormal collagen: skin, joint, vascular
What is Huntington's Disease?
Adult onset neurodegenerative disorder
: 1/10,000 individuals of European origin
Mutation in Huntington gene (amplification of trinucleotide repeat (CAG))
Confirmation of clinical diagnosis through DNA testing for CAG repeat size
Can test mutation in family members prior to clinical symptoms (ethical issues)
* with larger repeats, age of onset is sooner!
What are some examples of Autosomal Dominant Gene Mutations of the oral cavity?
: mild reduction in no. of teeth
: supernumerary tooth, usually between max incisors
Amelogenesis Imperfecta, hypocalcified type
: normal quantity of enamel, but soft
: 1/14,000 live births
- improper differentiation of ameloblasts --> brown color
Describe some features of autosomal recessive disorders.
: expression of phenotype requires inheritance of mutant allele from EACH parent
Phenotype observed among siblings of the proband, not parents, offspring, or other relatives
carriers have one normal allele and one mutated allele --> no phenotype
recurrence risk for each sib of proband is 1 in 4
What are some examples of autosomal recessive disorders?
Cystic Fibrosis (CF)
: abnormal ion transport protein
Sickle Cell Anemia
: abnormal hemoglobin
: enzyme deficiency (phenylalanine hydroxulase deficiency)
: copper metabolism
What are some symptoms of the autosomal recessive disease Ellis Van Creveld Syndrome?
short stature, shortening of forearms and lower legs
congenital heart malformations in 50%
dysplastic nails and teeth
mutations in EVC gene, chromosome 4, p16 responsible for phenotype
Describe inheritance patterns of X-linked diseases.
mutation of genes on x-chromosome
phenotypic expression generally in males
all daughters of affected males carry his x-chromosome, thus the mutated gene responsible for the condition
sons of carrier females are at 50% risk for inheritance of mutated gene
What are some oral cavity examples of x-linked diseases?
Amelogenesis Imperfecta - x-linked hypoplastic type
in males, thin smooth enamel
in females, enamel w vertical furrows, or hypoplastic depressions
What is "Lionizaiton" or the Lyon Hypothesis?
X and Y differ in size and number of genes
Single active X chromosome in mammals
mechanism for dosage compensation
*random inactivation of the maternal or paternal x chromosome early in female embryogenesis
fidelity of X-mat or X-pat inactivation in clonal descendents
skewing of x-inactivation --> could be tissue specific
Define genetic heterogeneity
Mutations of more than one gene cause the same disorder
(also defined later on in lecture as
: determined by a mixture of major/minor genes + environmental factors)
Define clinical heterogeneity
mutations in same gene cause different disorders
define de novo mutation
no family history
define variable expressivity
trait is expressed differently among individuals carrying the same mutant gene, even within a family
CL/P results from what?
single gene disorder
failure of lip closure (6-8 wks gestation) with secondary failure of palate closure (9-11 wks)
: 1 female
one of the most common birth defects
What are the different ways to get CL/P?
Isolated cases (75-80%); often multifactorial
familial, single gene forms (10-15%)
syndromic forms (1-5%); includes teratogenic exposure (rubella, meds)
What is the most common single-gene cleft syndrome? is it dominant or recessive? Symptoms?
Van der Woude Syndrome
associated w mutations in IRF6 (70% of cases)
* clinical heterogeneity (mutations also associated w Popliteal pterygium syndrome)
CL w/wo P, as well as clefting of uvula
lower lip pits (80%)
Hypodontia or missing lateral or central incisor
What is Holoprosencephaly (HPE)?
developing forebrain fails to divide into 2 separate hemispheres/ventricles
80% have associated craniofacial anomalies
: numerical/structural chromosome anomaly
: recognizable syndrome
: nonsyndromic HPE
Describe Nonsyndromic HPE
inherited autosomal dominant
often associated w chromosomal alteration
extreme variability of phentoype
- single central incisor
- midfacial hypoplasia
- cleft lip
Mutations in more than 4 genes account for 40-50% of Nonsyndromic HPE
What are some signs of Amelogenesis Imperfecta (AI)
clinical and genetic heterogeneity
at least 14 distinct subtypes based on clinical appearance and inheritance, with varying modes of inheritance
- defect of dental enamel formation
- teeth are small, discolored, grooved or pitted, and prone to rapid wear and breakage
What are the four main types of AI?
Describe Osteogenesis Imperfecta (OI)
group of genetic disorders due to improper formation of type I collagen
Range in severity from lethal (in utero, type II) to extremely mild (type I)
- multiple fractures
- short stature
- hearing loss
- blue sclera
- dentinogenesis imperfecta
What are some clinical features of Dentinogenesis Imperfecta (DI)?
Characteristic tooth crown color:
- blue-gray or yellow-brown and translucent
- caused by defective, abnormally- colored dentin shining through overlying enamel - "opalescent dentin"
- underlying defective dentin not able to adequately support the unaffected enamel
- often flakes off
Name 2 types of DI.
: associated w Osteogenesis Imperfecta -> caused by defects in the 2 genes encoding type I collagen
: most common type. No increased frequency of bone fractures --> caused by mutation in DSPP gene, inherited in autosomal dominant pattern
When DI is found by itself, it is considered to be "x". When it travels in combination with multiple medical findings, it is considered to be "y"
What is ectodermal dysplasia?
Primary defect in the development of 2+ tissues derived from ectodermal layer (ie hair, skin, nails and teeth)
>190 clinically distinct syndromes associated w ectodermal dysplasia
Describe Ectodermal Dysplasia 1
usually inherited as x-linked recessive
caused by mutation in Ectodysplasin A gene (ED1)
Characteristic facial abnormalities:
- prominent forehead
- sunken nasal bridge "saddle nose"
- unusually thick lips
- large chin
eye abnormalities, decreased tearing
partial or complete absence of eccrine sweat glands --> leads to lack of or diminished sweating, heat intolerance, fever
soft, thin, dry skin
skin peeling/scaling (newborn) and eczema
fine, brittle and scant hair (hypothrichosis)
absent or scanty eyelashes and eyebrows
oral manifestations of ED1
Malformation of certain teeth
- conical or pegged teeth
- hypodontia or complete anodontia
- delayed eruption of permanent teeth
Jaw radiographs indicated for infants with fever of unknown origin and family history of EDS
- perform orthopantography at an early age if hypodontia or dental abnormalities are present
What is Cowden Syndrome? What are some clinical features?
Multiple hamartoma syndrome
- autosomal dominant
- age-related penetrance (90-95% by 20 yrs of age)
- Increased risk factor for cancer (breast, thyroid, endometrial)
- gingival and palatal lesions (benign fibromas); cobblestone appearance
- thickening or furrowing of the tongue (fissured)
- multiple skin tags
- subcutaneous lipomas
What is FAP? Inheritance pattern? Clinical features?
Familial Adenomatous Polyposis
- autosomal dominant inheritance
accounts for 1% of ALL colorectal cancer
caused by mutations in APC tumor repressor gene
30% of patients have de novo germline mutations
- 100-1,000s of adenomas by early adulthood
- untreated polyposis leads to 100% risk of colorectatl cancer
- risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain)
What is Gardner's Syndrome?
A variant of FAP
- desmoid tumors
- supernumerary teeth
- soft tissue skin tumors