Med Gen Exam

AGGHHHHHHH

genetics

the study of heredity or how the characteristics of living organisms are transmitted from one generation to the next via DNA

when do most kids roll over?

4 months

when do most kids sit?

6 months

when do most kids talk?

12 months

when do most kids walk?

18 months

when do most kids name colors/friends?

2.5 yo

when do most kids dress themselves?

3.5 yo

if a child is under 5 years old and behind in 2 or more categories they are classed as having:

global delays

if a child is 5 or older and behind in 2 or more categories they are classed as having:

intellectual disability

what percentage of pediatric hospital patients have genetic components to their admission?

70%

eugenics

a pseudoscience claiming complex human traits can be improved through selective breeding

eugenicists believed

• complex traits were solely genetic and mendelian (intellect, mental health, crime propensity)

• selective breeding should be used to improve the quality of the human race

• forced sterilization of undesirables

what percent of the genetic code is identical between any two people?

99%

chromatin

DNA + folding proteins (histones/nucleosomes)

chromosome

chromatin + folding proteins

chromatid

one of two identical halves of a chromosome that has been replicated

missense variant

a change in a single nucleotide causing a protein to have a different amino acid than normal

nonsense variant

a change in a single nucleotide causing a protein to end prematurely

silent variant

a change in a single nucleotide that does not change the protein

frameshift variant

a deletion or insertion causing a protein's reading frame to change, every amino acid downstream changes and usually this results in a premature stop codon

gain of function variant

variants that increase the amount of normal protein (Down syndrome) OR variants that increase the normal function or create a new function for the protein (achondroplasia, Noonan syndrome, sickle cell anemia)

loss of function variant

variants that result in decreased/absent amounts of normal protein (most autosomal recessive conditions, monosomies, microdeletions)

dominant negative variant

variants that impair the function of the normal protein (osteogenesis imperfecta, Marfan syndrome, Brugada syndrome)

locus

location on a chromosome where a gene exists (ex: wing type gene on 3q22.1)

allele

alternate forms of the same gene (ex: B vs b)

genotype

the specific information encoded at a given locus in the genome (ex: BB vs Bb vs bb)

homozygous genotype

made up of two identical alleles (BB or bb)

heterozygous genotype

made up of two different alleles (Bb)

phenotype

the observable traits of an individual (normal wings vs wrinkled wings)

complete penetrance

all of the individuals who have a disease-causing variant will express the phenotype

incomplete penetrance

some of the people who have a disease-causing variant will express the phenotype and others will have no phenotype associated with it

variable expressivity

all of the people who have a disease-causing variant will have a phenotype but they have different signs, symptoms, or degrees of severity for the condition

incomplete penetrance and variable expressivity

some of the people who have a disease-causing variant will show a phenotype but the phenotype may be different for every individual (signs, symptoms, degrees of severity), some people with the variant will not show any phenotype though

pleiotropy

a single gene influences 2 or more unrelated phenotypic traits

locus heterogeneity

variants in several different genes cause the same phenotype (ex: Cornelia de Lange can be caused by pathogenic variants in NIPBL, RAD21, SMC3, BRD4, HDAC8, or SMC1A)

allelic heterogeneity

different variants within one gene cause the same phenotype (ex: cystic fibrosis is caused by 1000+ variants in CFTR)

gene

discrete section of DNA that encodes for a functional product

A paracentric inversion is more likely to result in liveborn with multiple anomalies than a pericentric inversion.

FALSE

What is the most common structural chromosome abnormality in humans?

Balanced Translocations

In which scenario is ordering a chromosomal analysis (karyotype) NOT the preferred test?

evaluation of a child with multiple congenital anomalies

constitutional

genetic changes present in virtually all cells of the body

acquired

genetic changes that develop in specific cells during a person's life rather than being inherited at birth (ex: cancer)

euploid

an individual contains the correct, normal number of chromosomes

aneuploid

an individual contains an abnormal number of chromosomes (missing or extra copy)

triploidy

2% of all conceptions and 10% of detected chromosomal abnormalities in spontaneous abortions, it is a fetus with three copies of every chromsome. can be due to diandric or digynic

diandric

triploid formed by an egg and 2 sperm, 85% of triploid fetuses. notably, an abnormally degenerative placenta with a small but proportional fetus

digynic

triploid formed by a diploid egg and one sperm, 15% of triploid fetuses. notably, a very small placenta and small fetus with macrocephaly

nondisjunction

failure of homologous chromosomes or sister chromatids to separate during meiosis

Robertsonian translocation

fusion of acrocentric chromosomes, usually producing pseudodicentric, 1 in 1000 births

most common is rob(13q14q) - 75%

second most common is rob(14q21q) - 10% - which is the primary familial down syndrome translocation

Balanced/Reciprocal Translocation

most common chromsomal abnormality in live births, 1 in 500, inherited 70%

they are asymptomatic, but recurrence risks are impacted

insertions

non-reciprocal translocations, 50% risk for unbalanced gametes

paracentric inversion

inversion in a region not including the centromere, more likely to result in miscarriage

pericentric inversion

inversion in a region including the centromere, more likely to result in liveborn infant with multiple anomalies

isochromosomes

abnormal chromosome where one arm is missing and replaced by an exact mirror-image copy of the other arm

ring chromsome

a circular piece of DNA that forms when a normal chromosome breaks in 2 places and the broken ends fuse together

copy number variants

the amount of genetic material at a specific segment of chromosome varies from expected amount, usually sized at 1000 to 3 million base pairs

recurrent CNV

break points are similar in unrelated individuals, with nonallelic homologous recombination being a key mechanism. there is often a reciprocal syndrome. (ex: 22q11.2 duplication/deletion syndromes, Williams/7q11.23 duplication syndrome, Smith-Magenis/Potocki-Lupski Syndrome

non-recurrent CNV

highly variable break points in unrelated individuals, with nonhomologous end joining as the presumed mechanism. usually not associated with a recognizable syndrome

nonallelic homologous recombination

paralogous regions cause misalignment which leads to recurrent dels/dups

nonhomologous end-joining

repairs double-strand breaks in DNA by directly sticking the broken ends back together without needing a template, can result in indels

adjacent-1 segregation (in balanced translocations)

non-homologous centromeres go to the same pole, which is the most frequent form of genetic imbalance in carriers of a reciprocal translocation

alternate segregation (in balanced translocations)

a meiotic pattern in individuals with a reciprocal translocation where two normal chromosomes go to one pole and two translocated chromosomes go to the opposite pole, producing genetically balanced and viable gametes

adjacent-2 segregation (in balanced translocations)

homologous centromeres move into the same new cell together

isodisomy

a person inherits two identical copies of a single chromosome (or part of a chromosome) from one parent, error in meiosis II

can be detected through CMA due to large region of homozygosity

heterodisomy

a type of uniparental disomy where a person inherits two different homologous chromosomes from one parent and no copy from the other, error in meiosis I

usually not detected by CMA

Trisomy 21 (Down syndrome)

most common aneuploidy and trisomy in liveborn (1 in 700), most common genetic cause of ID, 60 year life expectancy

symptoms: hypotonia, short stature, curved fifth digit, single palmar crease, mostly mild to moderate ID, atrioventricular canal defect, TE fistulas, duodenal atresia, Hirschsprung disease, distinctive facial features

Trisomy 18 (Edwards syndrome)

second most common trisomy in liveborn infants (1 in 5000), more common in miscarraiges than live pregnancies

75-95% mortality within first year

symptoms: poor prenatal growth, microcephaly, rocker bottom feet, hypertonia, clenched hands, micrognathia, severe ID, feeding deficiencies, hepatoblastoma, Wilms tumor (kidney), congenital heart defects (VSD)

Trisomy 13 (Patau syndrome)

third most common trisomy in live infants but most severe one

90% mortality within first year

symptoms: midline clefting, scalp defects (with skin not closing), exomphalos, holoprosencephaly, postaxial polydactyly, broad nose, severe ID, major developmental delays, heart defects, hypotonia

trisomy 16

the most common trisomy in fetuses, but none make it to birth

Turner syndrome (monosomy X)

most common aneuploid in fetuses, are 20% of chromosomally abnormal SABs, more than 95% of them are miscarried, only monosomy in live infants, 1 in 2500 females

symptoms: short stature, broad shoulders, Madelung differences, heart and kidney defects, mild cognitive differences

Klinefelter syndrome (47, XXY)

1 in 1000 male births, sometimes asymptomatic

symptoms: smaller genitalia, feminine shape, larger breasts, tall and slim

Which statement is accurate regarding chromosomal rearrangements?

Males with Robertsonian translocations have lower recurrence risks than females

Which of the following children is developmentally appropriate for their age?

1-month-old girl with no eye contact or vowel sounds.

What is a genome?

a complete set of an organism’s genetic material

What is true regarding Fragile X syndrome?

It's the most common single-gene cause of intellectual disability

________ chromosomal variation is present in all cells in the body, whereas ________ chromosome variation is present in a limited type of tissue, usually cancerous in origin.

constitutional; acquired

What term describes the physical expression of an organism's genes?

phenotype

What is the most common mechanism that results in trisomy of a chromosome?

nondisjunction in meiosis I

Which term is defined as a segment of DNA that is the basic unit of heredity which codes for a specific protein or set of proteins?

gene

What term is defined as the presence of 3 copies of each chromosome?

triploidy

The most common Robertsonian translocation:

rob(13q14q)

The diagnostic yield for exome/genome sequencing in patients with intellectual disability is around

30-40%

Which chromosomal microdeletion condition is presumed to be caused by nonhomologous end joining?

5p- (Cri-du-chat syndrome)

Babies born prematurely are at an increased risk of developing intellectual disability due to:

intraventricular hemorrhaging

______ results in the formation of gametes, whereas ______ results in the formation of identical daughter cells.

meiosis; mitosis

Allele

A version of DNA sequence at a defined genomic location

Which disorder causes severe hypotonia is on Newborn Screening?

Spinal Muscular Atrophy

What is the central dogma of molecular biology?

DNA → RNA → Protein

Which type of mutation involves the substitution of one nucleotide for another in DNA?

missense mutation

Which process is responsible for converting mRNA into a protein?

translation

What is the most common chromosomal abnormality in liveborn children?

Balanced translocations

developmental milestones

an ability that most children can achieve by a certain age

gross motor skills

independent sitting and walking

ex: sits without support at 9 months

fine motor skills

grasping spoons and holding crayons

ex: picks things up between thumb and pointer finger at 12 months

communication milestones

language and nonverbal communication

ex: turns head toward sound of your voice at 4 months

cognitive milestones

ability to think, learn, and solve problems

ex: watches you as you move at 2 months

social/emotional milestones

interactions with others and management of emotions

ex: smiles when you talk to them or smile at them at 2 months

developmental delay

when there is a significant delay in a particular developmental milestone

intellectual disability

significant limitations in both intellectual functioning (assessed through IQ test) and adaptive behavior (conceptual, social, and practical adaptive skills)

onset is before the age of 18

syndromic intellectual disability (syndromic ID)

where intellectual disability occurs as part of a larger syndrome and involves other medical and/or behavioral symptoms

ex: Fragile X, 22q11.2, Williams, Smith-Magenis, Prader-Willi, Angelman, Wolf-Hirschhorn, and 5p- syndromes