Human Disease Genes Flashcards
Define pleiotropy
mutations in a single gene can cause multiple disorders (distinct phenotypes)
Define genetic heterogeneity
A single phenotype can be caused by variants in multiple gene
e.g. hypercholesterolemia (APOA2, GHR, GSBS, EPHX2 and LDLR)
Define allelic heterogeneity
A single disorder caused by multiple mutations within the same gene
Define incomplete penetrance
Same variant allele but only some individuals express the associated phenotype
e.g. RB1, HTT -high, BRCA1 moderate, HFE hemochromatosis low
Define variable expressivity
The same genotype causes a wide range of clinical symptoms across a spectrum.
e.g. Two people have the same diagnosis and variant in NF1 but only one has all the features
*can be due to allelic heterogeneity
Give examples of TBX5 (T-box 5) pleiotropy
Holt-Oram syndrome (heart-hand) syndrome
Cardiac abnormalities
Limb anomalies
Give examples of NBN (nibrin) pleiotropy
Microcephaly
Immunodeficiency
Nigmegen breakage syndrome (cancer predisposition)
Give examples of PAH (F hydroxylase) pleiotropy
Phenylketonuria
Intellectual disability
Eczema
Pigment defects
Define missense variant
Causes substitution of one amino acid for another
Define nonsense variant
Causes premature stop codon
Define synonymous variant
Changes DNA and RNA, but not amino acid
Define splice-site variant
Causes exon skipping or read-through into intron
Define in-frame deletion/insertion
Deletes or inserts one or more amino acids
Define frameshift variant
Changes the reading frame (can result in premature stop)
Define indel
Small insertion and deletion of up to ~50 bp
Define stop loss
Normal termination is lost
p.Ter1481TyrextTer4
Define microsatellite polymorphisms
short tandem repeats
Dynamic variants in neurological disorders
Define copy number variants (CNVs)
Dosage imbalance of one or more genes
Approximately ___% of the genome is composed of single copy DNA sequences and ____% of the genome is composed of repetitive DNA
50%, 50%
The genome consists of _____% of coding sequences (exome) and ________ monogenic diseases
1-2%
6000
The human genome is composed of _______ base pairs
6 billion
The average genome contains around _____ very rare (<0.1%) coding variants and ____ variants previously reported as disease causing
200
54
The ____ and ____ polymerases are high fidelity and replicated the 6x10^9 bases in the human genome
delta and epsilon
____ other polymerases can carry out lower fidelity DNA synthesis during DNA replication or repair (99.9% of errors are repaired)
15
(alpha, beta, sigma, gamma, lambda, REV1, zeta, eta, iota, kappa, theta, nu, mu, Tdt and PrimPol)
On average there is less than ___ mutation per genome/cell division
one
1x10^-10
On average between _____ and ____ nucleotides are damaged per human cell per day
10,000 and 1 million
1 in ____ persons likely to receive a new mutation in a known disease gene from one or the other parent
200
What are the two types of nucleotide substitutions?
transition, transversion
A ______ is a pyrimidine to pyrimidine or purine to purine substitution
transition
A ______ is a pyrimidine to purine or purine to pyrimidine substitution
transversion
Although there are 2x more possibilities for transversions, what is the transition:transversion ratio?
60%:40%
A ____ to ____ transition is the most common point mutation. Mechanism?
C>T
Deamination of cytosine (through 5-methylcytosine and deamination or uracil methylation to T)
The _____ is a ribonucleoprotein (RNP) complex responsible for excision of intragenic regions from eukaryotic RNA polymerase II transcripts (precursors to mRNA)
spliceosome
The spliceosome utilizes ___ unique snRNAs and over _____ different proteins
9
300
The 5 prime splice donor is a ______ pair in the intron while the 3 prime acceptor is a ______ pair in the intron
5 prime: GT
3 prime: AG
Aberrant splicing and sequence variants that insert premature termination codons can lead to ______ _______ _______
nonsense-mediated decay (NMD)
Nonsense-mediated decay is an mRNA surveillance pathway that degrades mRNA that harbor ______ mutations and helps prevent production of _____ proteins that could result in disease
nonsense
truncated
Nonsense mediated decay will not occur if the premature stop codon is in the _______ exon or within ______ base pairs of the end of the ______ exon
last exon
50 bp of the end of the penultimate exon
Nonsense mediated decay will not occur for _______ exon genes
single
The premature stop codon is recognized by the ribosome and detaches from the mRNA but the _____ ____ ____ remain bound and signals remain bound and signal mRNA for destruction
exon-junction complexes
Two gene examples and the severity of phenotype based on the location of premature stop codons
SOX10: PCWH (peripheral demyelinating neuropathy central dysmyelination Waardenburg syndrome and Hirschsprung disease) vs Waardenburg syndrome 4 (haplonisufficiency)
SFTPB - neonatal to infant death (complete loss) whereas partial loss leads to later onset and longer survival
Four Consequences of Variants on Protein function and most common?
LOF (most common)
GOF (FGFR3 achondroplasia, BetaAPP, PMP22 - CMT, Hb Kempsey)
Novel property (IDH, HbS)
Dominant negative variants (collagen - multimer)
What are the 3 factors that affect expressivity and penetrance?
Global modifiers (threshold, polygenic, genetic compensation, NMD, FHx, age, sex, environment)
Gene expression (allelic expression, isoforms, cis/trans, somatic mosaicism, epigenetics)
Causal Variants (location, consequence and repeat expansion)
Genetic testing is performed to determine __________ to particular health condition in a ________ individual or to confirm a _________ of genetic disease in a __________ individual
predisposition (asymptomatic)
diagnosis (symptomatic)
_____ testing determine likely disease course/severity/response to treatment
Prognostic
________ testing is in an asymptomatic patient to determine risk of affected offpsring
Carrier
COL1A1 and Ehlers-Danlos syndrome is an example of pleiotropy: Give two examples of disease
Infantile cortical hyperostosis (Caffey disease)
osteogenesis imperfecta
________ genetics is a subdivision of genetics concerned with the structure and function of genes at the molecular level
Molecular
_________ genetics is the study of inheritance in relation to the structure and function of chromosomes
cyto
_________ is characterized by relative macrocephaly, short limbs and trident hand
Achondroplasia
*short-limbed dwarfism
1in 25,000 births worldwide
99% of achondroplasia is caused by a single mutation in the _______ gene
FGFR3
______% of achondroplasia is caused by de novo mutations
80%
Most common (99%) mutation in FGFR3 that causes achondroplasia
c.1138G>A, p.Gly380Arg
A newer version of gel electrophoresis, restriction digest, sequencing that uses FRET/quencher
Taqman PCR
Lynch syndrome is an autosomal ______________ cancer predisposition syndrome
(autosomal) dominant
What 4 cancers are associated with Lynch syndrome?
- Colorectal
- Endometrial
- Ovarian
- Gastric
Lynch syndrome is also known as __________ ___________ _________ syndrome
hereditary nonpolyposis coli syndrome (HNPCC)
What are the 4 Amsterdam II criteria for Lynch syndrome?
- Three affected first degree relatives
- Two successive generations affected
- One or more HNPCC cancers before 50
- Negative of APC mutation or familial adenomatous polyposis (FAP)
In HNPCC the _________/________ heterodimer recognizes the defect
MSH2/MSH6
In HNPCC the _________/________ heterodimer repairs the defect
MLH1/PMS2
90% of HNPCC is caused by mutations in ________ and ________
MLH1 and MSH2
7-10% of HNPCC is caused by mutations in _________ and <5% is caused by mutations in ________
MSH6
<5% in PMS2
Microsatellite instability is caused by defective ______ _______ ________
mismatch repair (dMMR)
MSI is caused by _________ mutations in MSH2, MLH1, MSH6 and PMS2
germline
PCR product sizing is done by ______________ ______________ and ___________ ________ (old school)
capillary and gel electrophoresis
Risk of HNPCC in nonpolyposis CRC a priori and with MSI-H?
2-5% (a priori)
20% (MSI-H)
Lynch syndrome risk by age 70
1. CRC
2. Endometrial
3. Ovarian
- 50%
- 20%
- 25%
The third step of MPS is sequencing by _________
synthesis
The first step of MPS is ___________ preparation
library
The second step of MPS is _________ ___________
bridge amplification
The fourth step of MPS is ________________
alignment and mapping
The fifth step of MPS is _________________
annotation
_________ and ____________ files hold sequencing information and/or quality scores
FASTA
FASTQ (quality)
__________ files have alignment information
SAM
sequence alignment map
3 things that MPS does well
mutations and short deletions or insertions
4 things done poorly by MPS
- Large dels/ins
- Structural rearrangements
- Repeat tracks
- Pseudogenes
The average fragment length of MPS is < ____________ bp
< 200 BP
Most common shearing techniques for MPS are _________ and _________
physical
enzymatic
**focused acoustic shearing
Gene responsible for dopa responsive dystonia
GCH1
guanine triphosphate cyclohydrolase I
Abbreviation for coding sequence change
c.
Abbreviation for protein sequence change
p.
The ______________ has guidelines for interpretation of variants
ACMG
American College for Genetics and Genomics
The _____________ has guidelines for naming variants
HGVS
Human Genome Variation Society
What is the nomenclature for a frameshift ending in 4 codons
fs*4
The 5 prime splice donor is an _________
GT
The 3 prime splice acceptor is an __________AG
AG
Coding and Protein variants are ascribed to the farthest _______ prime position as possible
3 prime
Cystic fibrosis is an autosomal _____________ disease with a carrier rate of 1 in 25 and a prevalence of 40,000 in the US
recessive
Cystic fibrosis is caused by mutation in ______________ on chromosome __________
cystic fibrosis transmembrane conductance regulator
chromosome 7
CF can cause __________ and thus infertility in 95% men (infertile, not sterile)
CBAVD
Congenital bilateral absence of the vas deferens
CF can cause neonatal ________ ___________ (obstruction) and prenatal ___________ obstruction
meconium ileus
prenatal bowel obstruction
CF can cause ____________ pancreatic insufficiency (88%) and CF-related _______________ (18%)
exocrine
diabetes (endocrine)
CF causes lung disease in ________% of patients and chronic sinus disease in _____% of patient
100%
38%
CF can cause growth failure from malabsorption of vitamins __________________
D,E,A and K
CF patients have a __-___x higher risk of colon cancer and ____-______x higher risk after transplantation
5-10x higher CRC
25-30x after transplant
The median survival for CF is now ________ years whereas it used to be less than 20 years
61
Newborn test for CF due to partial pancreatic blockage
immunoreactive trypsinogen
Besides trypsinogen, what are the two other tests for CF?
sweat chloride
sequencing - biallelic pathogenic CFTR mutations
CF requires an elevated sweat chloride test of > _____ mmol/L
60
0-29/39 unlikely
CF mutation analysis is usually a ______ variant screen
39 variant
__________ testing is the gold standard for CF
sweat
_________ is utilized to stimulate localized sweating for CF sweat test
pilocarpine
CF-related metabolic syndrome/ CF screen positive indeterminate diagnosis (CRMS/CFSPID) with IRT and nl/int sweat chloride and heterozygous/negative CFTR mutants should be monitored until age ___________
8
CFTR is a _________ regulated ____________ channel
cAMP
chloride
CFTR stands for ______ __________ _________ __________ __________
cystic fibrosis transmembrane conductance regulator
CFTR-related disorders (CFTR-RD) have _________ CF mutations + CF features in at least one organ system (CBAVD, disseminated bronchiectasis, pancreatitis) + normal/borderline sweat chloride and milder phenotype and unknown spectrum of risk
biallelic
CFTR maintains hydration of secretions within airways and ducts through the release of cellular ______ and the inhibition of _________ uptake
chloride
sodium
In CFTR ____________ or compound _________ mutations cause disease
homozygous
compound heterozygous
Over 70% of all CF patients have at least one _________ mutation
ΔF508
p.Phe508del
c.1521_1523delCTT
38% homozygous
The ΔF508 CFTR mutation is most common in the _____________ population
white
Class III CFTR defects are ____________ defects or _________ opening defects
regulatory
channel opening
The CFTR ΔF508 mutation is a class __________ CFTR and results in ________________
class II
protein misfolding
Class IV CFTR defects are _____ ____________ defects
ion transport
R117H
Class I CFTR defects are a result of ________________
lack of CFTR protein synthesis
nonsense mutations
splice site
Class V CFTR defects are ____________ ____________ defects
protein synthesis
5T
splice sites
promoters
Class VI CFTR defects are protein ______ _______ defects
half life
Class ____ to _____ CFTR defects have classic CF phenotype
I to III
Class _______ to _______ CFTR defects have late-onset or mild phenotype (CFTR-RD) or pancreatic insufficiency
IV to VI
In 2023 ACMG expands min. CF variant set to ______ to achieve 95% carrier detection rate across 6 ancestral populations
100
R117H can cause an ion transport or class ______ CF defect with the ____T tract in cis
IV, 5T
R117H can cause CFTR-RD with the ______T tract
7T
Longer polyT = more normal function
R117H may or may not be associated with the lung disease of cystic fibrosis
Phenotypic expression depends on the presence of a polyT tract and poly TG tract in intron ____
intron 8
The penetrance of the 5T poly T tract (and thus R117H phenotype) is determined by a 5 prime uptream _______ _____ sequence where the ________ the repeats the more penetrance of disease
poly TG
longer (13 > 12 > 11)
Determining whether the R117H and 5T occur in cis is called _________ and should prompt testing of family members
phasing
______/____ w/o R117H can behave as CF-causing and in trans with severe CF mutation or homozygous 5T can cause CBAVD, CFTR-RD, or CF
5T/TG13
___________(ivacaftor, elexacaftor) help open channel and increase ion transport
Class III-V CFTR mutations (G551D)
potentiators
____________________ (elexacaftor, tezacaftor, lumacaftor) help with protein folding and transport to cell surface
Class II (ΔF508)
correctors
____________ are the most common monogenic disease in the world, 5% of world are carriers
hemoglobinopathies
_______ _______ _______ was the first disease to be characterized at the molecular level and remains among the best characterized of all inherited disorders
sickle cell disease
~______ million molecules in each RBC
270
Alpha globin is on chromosome ______ and regulated by ____________
chromosome 16
HS-40
Beta globin is on chromosome ______ and regulated by the __________
chromosome 11
LCR - locus control region
3 hemoglobins of embryonic life and their chains
Gower 1 - ζ2ε2
Gower 2 - α2ε2
Portland - ζ2γ2
Fetal hemoglobin chains
α2γ2
Hemoglobin A and A2 chains
HbA alpha2beta2
HbA2 alpha2delta2
____________ are quantitative reduction of globin chain production
thalassemias
Hemoglobinopathies are detected using ________ ____________ and ________
Gel electrophoresis
HPLC
alpha2gamma2 persistence after birth — called?
Hereditary Persistence of Fetal Hemoglobin (HPFH)
clinically benign
There are over _____________ structural Hb variants
1000
What are the HbS, HbC and HbE mutations?
HbS - Glu6Val
HbC - Glu6Lys
HbE - Glu26Lys
HbS in low oxygen state sickles and causes ______________ anemia and can cause vaso-occlusion and ___________
hemolytic
ischemia
______ ______ ________ is the major cause of morbidity and mortality in SCD
Acute chest syndrome
Prophylactic ____________ in children with SCD significantly reduces infection
penicillin
SCD reduces life expectancy to ____________ years and is a major cause of death in kids under _______________
53
5
Hydroxyurea reduces ACS through increased expression of _______________ which reduces HbS polymerization and sickling
HbF (alpha2gamma2)
Treatment for HbS transfusion iron overload
Chelation therapy
Curative treatment (1 old and 2 new) for HbS
bone marrow transplant
Lyfgenia (lentiviral gene therapy) - HBB gene
Casgevy (CRISPR-Cas9) - BCL11 disruption
Casgevy (CRISPR-Cas9) works by inhibiting _____________ which serves to inhibit ____________ production
BCL11
HbF (a2g2)
Sickle cell trait in HbS/HbA has higher risk for _________ infarction and renal ____________ carcinoma
splenic infarction
renal medullary carcinoma
Ethnicities most at risk for HbS?
African and mediterranean
Ethnicities at risk for alpha thalassemia?
Asians and mediterranean
Ethnicities at risk for beta thalassemia?
All other than N. European
HbS/HbA shows improved fitness over HbA/HbA for which parasite infection?
plasmodium/malaria
HbS (Glu6Val), HbC (Glu6Lys) and HbE (Glu26Lys) have autosomal _________ inheritance?
recessive
In thalassemias, whatever globin chain is in ___________ leads to precipitation
excess
Do beta globins have any prenatal consequences?
No
HbF is a2g2
The most common mutations in alpha thalassemia are ____________?
Deletions
Most common alpha thalassemia is called hemoglobin ___________ ______________?
Constant Spring
______________ is used to detect alpha thalassemia deletions
Multiplex ligation-dependent probe amplification (MLPA)
Hemoglobin disease with 2 alpha deletions and mild microcytic anemia
alpha thalassemia minor
Hemoglobin disease with 1 alpha deletion
carrier - asymptomatic
Hemoglobin disease with 3 alpha deletions, splenomegaly, hemolytic and microcytic anemia
HbH
Fetal condition with 4 alpha deletions
Hydrops fetalis
from heart failure
in utero death
Mechanism of 95% of alpha thalassemia or alpha deletions
Homologous recombination with unequal crossovers
HbH ________ ___________ is a more severe form of HbH
Constant Spring
The most common non-deletional hemoglobin alpha deletion
Hemoglobin Constant Spring (HbCS)
Hemoglobin Constant Spring (HbCS) is caused by what mutation
stop codon mutation
results in abnormally long hemoglobin alpha
HbH Constant Spring requires regular ______________________ and has a higher risk of _____________
transfusion
thrombosis
HbH can have hepatosplenomegaly, require __________ in asplastic crises and have _________ changes
transfusion
bony (maxillary hypertrophy, skull bossing)
Beta thalassemia is a result of ___________ mutations
point
β0 = little to no β synthesis
β+ = some β produced
Hgb Barts has four ___________ chains as a results of deletion of 4 alpha chains
gamma4
β-thal shows relative increased levels of Hb______ even after birth
HbF
Categorization of beta thalassemia?
minor, intermedia, major
Beta thalassemia may have mild ____________ and _________
mild microcytosis
mild anemia
Beta thalassemia _____________ likely has a moderate anemia and may become transfusion dependent and be treated with _____________ for HbF
intermedia
hydroxyurea
Small amounts of normal beta globin (HbA) produced (β0/ β+)
Untreated beta-thalassemia major has a _____% mortality by 5 years
80%
Beta-thalassemia major has hepatosplenomegaly, _________ expansion from ineffective hematopoiesis, cardiomegaly/HF and ____________ overload
marrow expansion
iron overload (GI absorption, independent of transfusion)
Two old treatments for beta-thalassemia major and two new treatments
Transfusion
BM transplant
Zynteglo (HBB)
Casgevy (CRSPR-Cas9) - BCL11 inhibition of inhibition of HbF production
With a fully _____________ condition, every affected individual will have inherited the condition from an affected individual
penetrant
Rare mutations include ______-_________ regulatory mutations, insertion of a ___________or __________ element (disrupting transcription or interrupting the coding sequence and _________ ______mutations (repeat sequences)
long-range
LINE or Alu (SINE)
tandem repeat (disorders)
50% of all human genetic mutations are _______ mutations while 25% are _____________
50% missense (aa substitution)
25% additions/deletions
Approximately 10% of all human genetic mutations are _________ mutations, another 10% are ___________ processing mutations and another 10% are _________-site mutations
10% nonsense
10% RNA processing mutations
10% splice-site
Only 5% of human genetic mutations are larger gene deletions, inversions, fusions, and duplications and this may be mediated by DNA sequence _______ either within or between strands
homology
Lynch syndrome (MMR) and LDLR are examples of genes with ________ inheritance paterns
two
____________ is when 50% protein function causes the phenotype
haploinsufficiency
ex. WAGR -PAX6 and WT1
-microdel syndromes
What does LOEUF stand for? What is it used for?
loss-of-function observed/expected upper bound fraction (LOEUF)
Genes with a high probability assignment (≥0.9) to the haploinsufficient class are classified as ‘extremely loss-of-function intolerant.
WAGR haploinsufficiency genes and phenotypes?
PAX6 - aniridia
WT1 - tumor suppressor - Wilms tumor
_______________ is a genetic condition that occurs when an extra copy of a gene is present, resulting in a phenotype. It’s the opposite of haploinsufficiency, which is when one copy of a gene is lost.
Triplosensitivity
50% of CMT patients have a duplication at 17p11.2 where the ______ gene is located and this results in triplosensitivity
PMP22
Tumor suppressor genes have autosomal __________ inheritance at the level of the organism and autosomal __________ inheritance at the level of the tumor
AD - organism
AR - tumor (double hit)
The classic double hit hypothesis tumor is ___________________
retinoblastoma
A __________ _________ mutation occurs when a single mutation eliminates the function of the protein encoded by one allele and also impairs the function of the normal protein
dominant negative
What at are the genes for dominant negative mutations which cause osteogenesis imperfecta and Marfan syndrome?
OI - COLA1 (Chr17) and COLA2 (Chr7)
Marfan - FBN1 (Chr 15)
Gain of function mutations are also called ___________ and are usually involved in __________ _____________
hypermorphs
intracellular signaling
MEN1 (parathyroid, pancreatic and pituitary) is caused by a loss of tumor suppressor gene ________ on chromosome 11q13 while MEN 2A (pheochromocytoma, parathyroid adenoma, medullar thyroid ca) and 2B (pheochromocytoma, marfanoid habitus and mucosal neuromas) are caused by gains of function of the ________ gene on chromosome 10
MEN1 (menin) Chr 11q13
RET Chr 10
_______ gain of function variants are autosomal dominant and result in excessive degradation of LDLR causing hypercholesterolemia and vascular disease
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
*protease
A ____________ is when the protein encoded by the mutated gene has a new effect that is not related to its typical function (IDH1/2, HDD)
neomorph
There is a roughly 1 in a ________chance per gene per generation of a de novo mutation
million
*some higher
________ 1138G is one of the most mutable positions in any gene and accounts for 99% of achondroplasia cases
FGFR3
____% of achondroplasia mutations have a de novo mutation and the incidence increase with _______ age
80%
paternal age
Somatic _____________ variants are dominant variants that would not be compatible with life if they were present in all tissues
mosaic
Sturge Weber is caused by somatic autosomal dominant mutations in the ____________ gene on chromosome 9 and results in somatic mosaic variants
GNAQ
Blood groups are an example of __________________ inheritance
codominance
_______________ diseases are rare and do not show strict Mendelian inheritance with variable penetrance but possibly multiple rare variants in the same pathway
Oligogenic
An example of oligogenic disease includes ___________ syndrome which is characterized by Idiopathic/Congenital hypogonadotropic hypogonadism (CHH) with anosmia
Kallmann Syndrome
FGF17, IL17RD, DUSP6, SPRY4 and FLRT3
Kallmann syndrome inheritance
partially sex-limited phenotype
males:females 4:1
Kallmann syndrome X-linked gene is ____________
KAL1 (anosmin) - axonal migration of GnRH and olfactory neurons
3-6% of patient
*females may express and secrete more anosmin than males - more toleratnt to dirsuptions of FGF8/FGFR1 signaling
The following disease are examples of ___________ inheritance: Long QT, hearing loss, Usher, Bardet Biedl (ciliopathies), Hirschsprung and retinitis pigmentosa
Digenic
Long QT (KCNH2 and SCN5A)
Usher syndrome (MY07A and CDH23 but 6)
Bardet Biedl (BBS1 and BBS10)
Hirschsprung (RET, EDNRB, ,EDN3, SOX10)
RP (RDS and ROM1 gene)
A ___________ effect in polygenic diseases is a phenomenon where a phenotype develops when a critical factor’s level or activity falls below a certain
threshold
In Hirschsprung threshold effect a _____________ proband with long-segment HSCR increases the risk for a male sibling
Female
*also 1% vs 3% for female sibling with short-segment
In Hirschsprung threshold effect a male proband with long-segment HSCR increases the risk for a male and female sibling by how much?
Male proband
Male sibling 5% SS HSCR to 17% LS HSCR (3x)
Female sibling SS HSCR 1% to 13% LS HSCR (13x)
