Genetic Disorders Part 2 Flashcards
what are complex multigenic disorders
- multifactorial or polygenic disorders
- variant gene + environmental factors
examples of complex multigenic disorders
- diabetes mellitus type 2
- congential heart disease
- cleft lip
what do you exclude when diagnosing multifactoral or polygenic disorders
- exclude Mendelian disorder
- exclude chromosomal mode of inheritance
what is a karyotype
- cells in metaphase
- chromosomes are arranged in decreasing length
when stain is used for katyotype
- Giemsa stain = G banding
- gives you light and dark bands
normal human chromosome #
46
(2n=46)
n= 23
what is euploid
2n
what is polyploid
3n
4n
what is aneuploid
not an exact number of n
what are cytogenetic disorders
- spontaneous abortions (50% due to chromosome abnormality)
- change in # and structure of chromosomes
which chromosomes do cytogenetic disorders affect
autosomes and sex chromosomes
what are the types of chromosomal rearrangements
- translocation (reciprocal/ balanced. Robertsonian)
- deletion
- isochromosome
- inversion
- ring chromsome
what is mosaicism
same individual 2 or more population of cells
- different complements of chromosomes
- mosaicism is common in sex chromosomes
what are the cytogenetic disorders involving autosomes
trisomy 21 (Down Syndrome) 22q11.2 Deletion Syndrome Trisomy 18 (Edwards Syndrome) Trisomy 13 (Patau Syndrome) Deletion 5p (Cri du chat Syndrome)
karyotype of trisomy 21
21:47XX, +21 (95%)
what is the translocation type of trisomy 21
46XX der (14;21)(q10:q10) + 21 (4%)
what is the mosaic of trisomy 21
46XX/47XX, +21 (1%)
what are the 2 candidate genes for trisomy 21 (chromosome 21)
DYRK1A codes for a serine-threonine kinase
RCAN1 regulator of calcineurin 1
characteristics of Trisomy 21
- epicanthic folds, flat facial profile
- redundant neck skin; Simian crease
- mental retardation
- congenital heart disease (VSD, ASD)
- acute leukemia (ALL, AML)
- intestinal stenosis, umbilical hernia
- Alzheimer disease
characteristics of Trisomy 18 (Edward Syndrome)
- prominent occiput
- mental retardation
- micrognathia
- clenched fist
- IUGR (intrauterine growth retardation)
- polyhydramnios
characteristics of Trisomy 13 (Patau Syndrome)
Microcephaly Mental retardation Cleft lip Cleft palate Polydactyly –extra digits Cardiac defects –mostly VSD Renal defects
what is 22q11 Deletion syndrome
intestinal deletion: 22q11.2
what 2 previous diseases were 22q11 Deletion Syndrome
DiGeorge syndrome Velocardiofacial syndrome (VCFS)
what is DiGeorge syndrome
T cell immunity, hypocalcemia
what is VCFS
dysmorphology, cardiac defects
22q11 Deletion Syndrome can causes
Schizophrenia
what is CATCH 22
Cardiac defects Abnormal face T cell immunity abnormal/Thymic hypoplasia Cleft palate Hypocalcemia 22q11 deletion
what is Del (5p) Cri du chat
terminal deletion of chromosome 5
characteristics of Del (5p) Cri du chat
“cat-like” cry
laryngeal hypoplasia
microcephaly
mental retardation
what are 2 cytogenetic disorders involving sex chromosomes
- Klinefelter syndrome
2. Turner syndrome
what is the karyotype of Klinefelter syndrome
XXY
what is the mosaic pattern of Klinefelter Syndrome
46,XY/47, XXY, 47,XXy/48,XXXY
Klinefelter syndrome results in
male hypogonadism
- testicular atrophy
- impaired spermatogenesis
- reduced hair
- low serum testosterone
Klinefelter syndrome increases the frequency of obtaining
Breast cancer
SLE
Extragonadal germ cell tumor
Leydig Cell Tumor
what are the single-gene disorders with atypical patterns of inheritance
- Triplet repeat mutations
- mutations in mitchondrial genes
- alteration of imprinted regions of genome
name an example of triplet repeat mutations
Fragile X syndrome
Xq27.3
what gene is mutated in Fragile X syndrome
FMR1 gene mutation
Fragile X syndrome has an amplification of
CGG repeat
-amplification during oogenesis
Fragile X syndrome
normal: 29 CGG
premutation: 55 to 200
Oogenesis = CGG expansion
Full mutation: greater than 200 repeats
Fragile X syndrome: carrier males transmit
- normal males
- phenotypically normal
- grandchildren are affected
- at risk for FX Tremor Ataxia syndrome (FXTAS)
Fragile X syndrome carrier females
30%-50% are affected
-primary ovarian failure
Fragile X syndrome anticipation
manifestations worsen with successive generations
what can cause Fragile X Syndrome
Neurodegenerative manifestation
Ataxia
Macroorchidism
Abnormal facial features
how do mutations in mitochondrial genes occur
- mitochondrial DNA
- maternal inheritance
- transmitted to all offspring - daughters transmit DNA to progeny
- sons do not transmit the DNA
- phenotypic variation
where is mitochondrial DNA
- Brian, ovary, skeletal muscles
- oxidative phosphorylation
- electron transport chain
what is Leber hereditary optic atrophy (LHON)
- prototype disorder
- transmitted though mother
- mitochondrial NADH dehydrogenase 1 (MT-ND1)
- causes oxidative phosphorylation
- loss of vision
what diseases caused by alterations of imprinted genes
- Prader-Willi Syndrome
2. Angelman Syndrome
what is genomic imprinting
- an epigenetic process (not a mutation!)
- differential inactivation
- paternal genes
- materal genes
how does genomic imprinting occur
- methylation of the gene promotor
- modifications of DNA binding proteins
- silencing of the gene
- maternal imprinting
- paternal imprinting
what gene is deleted in Prader-Willi Syndrome
-interstitial deletion of 15q12
Prader-Willi Syndrome affects
paternal chromosome
characteristics of Prader-Willi Syndrome
short stature, small hands, feet; hypogonadism
what gene is deleted in Angelman Syndrome
interstitial deletion of 15q12
what happens to the maternal chromosome in Angelman Synrome
maternal chromosome is silenced
characteristics of Angelman Syndrome
-mental retardation, ataxia, inappropriate laughter
what is the Angelman gene
-maternally derived
UBE3A - a ligase in ubiquitin-proteosom proteolytic pathway
