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At what stage is clinical cytogenetics captured?
- Cell genome at metaphase
- constitutional karyotype
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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
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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
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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)
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What's a characteristic phenotype of Trisomy 21?
- short stature
- microcephaly
- small mouth, oral cavity -> tongue thrusting
- epicanthic folds
- cardiac anomaly
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Which 3 trisomies are positively correlative with advanced maternal age?
21, 18, and 13
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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: 1%
- Amniocentesis:
- - performed at 15-18 wks
- - amniotic fluid contains true embryonic (fetal) cells
- - in situ cell culture: 5-10 days
- - procedure-related risk for miscarriage: 0.5%
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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
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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)
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Name some dental anomalies of Downs
- 30-50% have microdontia: affects primary and secondary dentition
- Additional features:
- - supernumerary teeth
- - abnormal spacing
- - crown variants
- - hypoplasia and hypocalcification
- - delayed eruption
- Increased risk of periodontal disease
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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
- Terminal deletions
- Interstitial microdeletions
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What are some prime examples of a microdeletion? What type of genetic testing would you employ to diagnose this?
- (aka: 22q11)
- DiGeorge/Velocardiofacial syndrome
- Opitz syndrome
- Conotruncal anomaly face syndrome
- **USE FISH testing, as karyotypic wouldn't show the deletion
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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
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What is the spectrum of findings of the 22q11 deletion syndrome?
- cardiac abnormalities
- palatal abnormalities: velopharyngeal incompetence (VPI), cleft palate, CL & CL/P, submucosal cleft, bifid uvula
- facial features: long, narrow face, beaked nose
- LD
- Immunodeficiencies
- Others: feeding problems, renal, hypocalcemia, hearing loss
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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
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Describe Microarray technology
- comparative genomic hybridization
- CHIP technology
- 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
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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: spacing)
- - can be used to characterize chromosome abnormalities detected by karyotyping (specific size of imbalance and genes involved)
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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
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What are some characteristics of Monogenic, Mendelian Disorders?
- single gene defects
- usually expressed in childhood
- incidence: 0.36% in liveborn population
- 1-3% of children have congenital malformation
- heritable genetic disorders
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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
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Name some examples of autosomal dominant genetic disorders
- Huntington's Disease: progressive neuronal degeneration
- Myotonic dystrophy: muscle weakness & wasting
- familial hypercholesterolemia: vascular disease
- osteogenesis imperfecta: fracturing
- marfan's syndrome: abnormal elastic tissue
- retinoblastoma: malignant tumor of eye
- Ehlers-Danlos syndromes: abnormal collagen: skin, joint, vascular
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What is Huntington's Disease?
- Adult onset neurodegenerative disorder
- Incidence: 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!
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What are some examples of Autosomal Dominant Gene Mutations of the oral cavity?
- Familial Hypodontia: mild reduction in no. of teeth
- Mesiodens: supernumerary tooth, usually between max incisors
- Amelogenesis Imperfecta, hypocalcified type: normal quantity of enamel, but soft
- - prevalence: 1/14,000 live births
- - improper differentiation of ameloblasts --> brown color
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Describe some features of autosomal recessive disorders.
- Rare diseases: 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
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What are some examples of autosomal recessive disorders?
- Cystic Fibrosis (CF): abnormal ion transport protein
- Sickle Cell Anemia: abnormal hemoglobin
- Phenylketonuria (PKU): enzyme deficiency (phenylalanine hydroxulase deficiency)
- Wilson's Disease: copper metabolism
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What are some symptoms of the autosomal recessive disease Ellis Van Creveld Syndrome?
- postaxial polydactyly
- 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
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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
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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
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What is "Lionizaiton" or the Lyon Hypothesis?
- X and Y differ in size and number of genes
- Single active X chromosome in mammals
- functionally hemizygous
- 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
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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)
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Define clinical heterogeneity
mutations in same gene cause different disorders
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define variable expressivity
trait is expressed differently among individuals carrying the same mutant gene, even within a family
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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)
- 2 males: 1 female
- one of the most common birth defects
- *genetic heterogeneity
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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)
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What is the most common single-gene cleft syndrome? is it dominant or recessive? Symptoms?
- Van der Woude Syndrome
- Autosomal Dominant
- 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
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What is Holoprosencephaly (HPE)?
- developing forebrain fails to divide into 2 separate hemispheres/ventricles
- 80% have associated craniofacial anomalies
- 25-50%: numerical/structural chromosome anomaly
- 18-25%: recognizable syndrome
- Remainder: nonsyndromic HPE
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Describe Nonsyndromic HPE
- inherited autosomal dominant
- often associated w chromosomal alteration
- extreme variability of phentoype
- Microforms/mild expression:
- - microcephaly
- - single central incisor
- - hypotelorism
- - midfacial hypoplasia
- - cleft lip
- Mutations in more than 4 genes account for 40-50% of Nonsyndromic HPE
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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
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What are the four main types of AI?
- Hypoplastic
- Hypomaturation
- Hypocalcified
- Hypomaturation/Hypoplasia/Taurodontism
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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)
- Clinical features:
- - multiple fractures
- - short stature
- - hearing loss
- - blue sclera
- - dentinogenesis imperfecta
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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
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Name 2 types of DI.
- Type I: associated w Osteogenesis Imperfecta -> caused by defects in the 2 genes encoding type I collagen
- Type II: most common type. No increased frequency of bone fractures --> caused by mutation in DSPP gene, inherited in autosomal dominant pattern
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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"
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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
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Describe Ectodermal Dysplasia 1
- Christ-Siemens-Touraine syndrome
- 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
- normal intelligence
- 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
- spoon-shaped nails
- fine, brittle and scant hair (hypothrichosis)
- absent or scanty eyelashes and eyebrows
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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
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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)
- Clinical features:
- - gingival and palatal lesions (benign fibromas); cobblestone appearance
- - thickening or furrowing of the tongue (fissured)
- - multiple skin tags
- - subcutaneous lipomas
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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
- Clinical features:
- - 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)
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What is Gardner's Syndrome?
- A variant of FAP
- Extraintestinal lesions:
- - desmoid tumors
- - osteomas
- - supernumerary teeth
- - soft tissue skin tumors
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