Lecture 5: Developmental Genetics of the Human Brain Flashcards

1
Q

When does the development of neurons occur?

A

the first and second trimester

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2
Q

When does the development of astrocytes and oligodendrocytes?

A

during the third trimester and the first year of life

expansion of the glial cells, astrocytes and oligodendrocytes is dependent upon the pool of remaining neuronal progenitors and neuronal activity

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3
Q

When are the first neuronal circuits established?

A

established in the embryo shortly after neurons are born

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4
Q

When are cerebral cortical areas established?

A

during the fetal period and remodeled during the first 2 years of life

throughout childhood, circuits are initiated, remodeled and stabilized as skills are learned and mastered

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5
Q

What are the rates of synaptogenesis and synaptic pruning in adults?

A

it is slow

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6
Q

What domains do chronic disorders affecting the central nervous system function during the developmental period?

A

motor skills
cognition
communication
behavior

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7
Q

What are some examples of neurodevelopmental disorders?

A

developmental delay and regression
intellectual disability
cerebral palsy
epilepsy
autism spectrum disorder
specific learning disabilities
language disorder
attention deficit/hyperactivity disorder
deafness
blindness

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8
Q

What are etiological factors causing neurodevelopmental disorders?

A

hypoxic-ischemic injury (during delivery brain lacks oxygen causes damage)

trauma

toxic exposure (could happen during pregnancy)

infections

immunologic factors

nutritional factors (not sufficient protein)

aging/maturation

iatrogenic disorders

oncologic disorders

genetic diseases (metabolic genetic, neurogenetic, structural brain malformations)

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9
Q

What are some examples of developmental domains?

A

gross motor
fine motor
speech/language
cognition
social/personal
activities of daily living

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10
Q

What is global developmental delay?

A

GDD is subset of developmental disabilities

> 2 SDs below age-matched peers in two or more aspects of developmental domains

heterogeneous etiology

estimated prevalence of GDD 1-3% in children <5 years of age

4 million newborns/year in US & Canada; 40,000-120,000 will manifest with GDD

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11
Q

When to suspect genetic diseases & consider a referral to a genetic clinic when viewing the medical history of a patient?

A

earlier age of onset of disease than expected
FTT/protein aversion
recurrent somnolence & coma
behavioral problems
seizures
hypotonia
loss of skills
ataxia/coordination problems
hair abnormalities
deafness
no other known or identified risk factors

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12
Q

When to suspect genetic diseases & consider a referral to a genetic clinic when viewing the family history of a patient?

A

ID/GDD
psychiatric disorders
congenital malformations
miscarriage/stillbirths/SIDS
early childhood deaths
maternal health
maternal side migraine/diabetes
parental consanguinity
ethnic predisposition to certain genetic diseases
other affected family members, suggesting Mendelian inheritance pattern

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13
Q

What are the implications of etiologic determination?

A

access to research treatment protocols

prognosis

ongoing medical management

assessment of recurrence risk

implementation of prevention programs

limiting further unnecessary testing

surveillance for known complications

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14
Q

What is inheritance?

A

genetic information is passed on from parent to child

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15
Q

What is the Human Genome Project (HGP)?

A

international research initiative between 1990-2003

the sequencing of the human genome involved researchers from 20 separate universities and research centers across the US, UK, France, Germany, Japan, and China

generated the first sequence of the human genome

studied several organisms e.g. E. coli, baker’s yeast, fruit fly, nematode and mouse

one of the most ambitious and important scientific endeavors in human history

produced a genome sequence that accounted for 92% of the human genome

about 20,500 genes in each human (the complete set of human genes)

location of all genes known in human genome

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16
Q

What is genotype?

A

individual’s actual DNA sequence at a specific locus (location on a chromosome)

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17
Q

What is phenotype?

A

observable ways in which that DNA sequence manifests in the individual, such as eye color, hair color, or susceptibility to a disease

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18
Q

What does allele mean?

A

an alternate form of a gene

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19
Q

What does wild-type mean?

A

an allele in its most common form in a population

20
Q

What does variant mean?

A

an allele that has a permanent alteration in its DNA sequence

called a mutation in old terminology

21
Q

What does homozygous mean?

A

two identical alleles

22
Q

What does heterozygous mean?

A

a single allele for a gene

23
Q

What is the terminology for variant classification?

A

pathogenic

likely pathogenic

VUS

likely benign

benign

24
Q

What is the terminology for variants in the category of phenotypes?

A

Variants in Disease Genes with an Established Association with the Reported Phenotype

Variants in Disease Genes with a Likely Association with the Reported Phenotype

25
Q

What are traditional Mendelian inheritance patterns?

A

autosomal recessive

autosomal dominant

X-linked recessive

X-linked dominant

Y-linked

26
Q

What are non-traditional (non-Mendelian) inheritance patterns?

A

complex, or multifactorial, inheritance such as genomic imprinting, unstable repeat expansions

mitochondrial inheritance

27
Q

What is the autosomal recessive inheritance pattern when both parents are carriers (Aa)?

A

1/4 children will be affected (AA)

2/4 children will be carriers (Aa)

1/4 children will be unaffected (aa)

28
Q

What is the autosomal dominant inheritance pattern when one parent is affected (Aa) and unaffected (aa)?

A

2/4 children are affected (Aa)

2/4 children are unaffected (aa)

29
Q

What is the X-linked recessive inheritance pattern when the father is affected (XY) and the mother is unaffected (XX)?

A

2 sons unaffected (X from mom, Y from dad)

2 daughters carrier (X from dad, X from mom)

30
Q

What is the X-linked recessive inheritance pattern when the father is unaffected (XY) and the mother is a carrier (XX)?

A

one son is affected (mutated X from mom, Y from dad)

one daughter is affected (mutated X from mom, normal X from dad)

one son unaffected (normal X from mom, Y from dad)

one daughter unaffected (normal X from mom, X from dad)

31
Q

What is the X-linked dominant inheritance pattern when the father is affected (mutated X, Y) and the mother is unaffected (XX)?

A

two sons unaffected (normal X from mom, Y from dad)

two daughters affected (normal X from mom, mutated X from dad)

32
Q

What is the X-linked dominant inheritance pattern when the father is unaffected (normal X, Y) and the mother is affected (normal X, mutated X)?

A

one son affected (mutated X from mom, Y from dad)

one daughter affected (mutated X from mom, normal X from dad)

one son unaffected (normal X, normal Y)

one daughter unaffected (normal X, normal X)

33
Q

What is the Y-linked inheritance pattern when the father is affected (normal X, mutated Y) and the mother is unaffected?

A

two sons affected (normal X from mom, mutated Y from dad)

two daughters unaffected (normal X from dad, normal X from mom)

34
Q

What is the importance of genetic testing?

A

for many families, simply having an answer for the cause of their child’s medical issues can be very powerful

at times, answering the “why” is a family’s primary motivation for pursing genetic testing

having a name for the condition allows them to find a peer group with parents of similarly affected children with whom they find shared experiences

many families unnecessarily harbor a great deal of personal guilt about their child’s condition, having the belief that they somehow caused their child’s medical issues

being able to provide a concrete genetic answer can alleviate that guilt and allows the family some closure

35
Q

How does specific genetic diagnosis provides prognostication for a patient’s future?

A

this can be particularly impactful for infants and small children who may have yet to manifest some of the comorbidities of the condition

allows for realistic expectations to be set with the parents and allows for directed care with condition-specific recommendations

the intention is to not set up a self-fulfilling prophecy, but rather ensure that all of the necessary support is in place to allow the individual to achieve to their maximum potential

36
Q

How does providing a genetic diagnosis can significantly impact family planning?

A

many couples are hesitant to expand their family without knowing the underlying cause of their child’s condition

once the genetic etiology is known, that information can be used to make an educated decision about if and how they decide to have more children

if they so choose, a specific gene variant can be used for pregnancy screening and/or in vitro fertilization

37
Q

What is traditional genetic testing?

A

preceded by a thorough physical examination, family history assessment, and other diagnostic workup to generate a differential diagnosis list

suspected conditions would then be tested “one by one” or at least “gene by gene”, an approach, which besides being costly and time consuming, is often ineffective due to the genetic heterogeneity of most inherited conditions

38
Q

What is chromosomal microarray?

A

broad, nonspecific, genomic test which analyzes the human chromosomes for large deletions and duplications (also called copy number variants or CNVs) of DNA

CMA has been considered the first-tier genetic test for children with multiple congenital anomalies (MCA), intellectual disability (ID), or developmental delay (DD), and autism spectrum disorders (ASD)

CMA has replaced the karyotype for children with these indications, largely due to the higher resolution and, therefore, higher diagnostic yield (15%-20%) for a microarray compared to a karyotype (~3%)

39
Q

What is diagnostic yield of chromosomal microarray in ID?

A

10.9% diagnostic yield in individuals with non-syndromic ID (10.7%)

11.1% diagnostic yield in non-syndromic developmental delay

40
Q

What is next generation sequencing (NGS)?

A

ability of simultaneously sequence a large number of genes (so-called gene panels)

exome sequencing (ES)

major shift from the classical sequential testing strategy into fast and more cost-effective “genomic” testing paradigms, oftentimes putting an end to lengthy diagnostic odysseys

41
Q

What are the advantages of genomic testing?

A

enables healthcare providers to accurately determine diagnosis, prognosis and recurrence risks

powerful in identifying patients who are candidates for the rapidly growing personalized targeted treatments and gene therapy for previously uncurable genetic conditions

increase in the utility of genetic testing

however limited access to clinical geneticists

most healthcare providers must become familiar how to obtain genetic testing

42
Q

What do you have to consider when determining which genomic testing strategies to use on a patient?

A

technology (sequencing, microarrays, methylation, etc.)

diagnostic yield

cost

turnaround time

whether testing should be targeted to a few genes or scaling the analysis to include the exome of genome in search of diagnosis

43
Q

What is exome sequencing (ES)?

A

genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome)

44
Q

What are the two steps of exome sequencing?

A

the first step is to select only the subset of DNA that encodes proteins

these regions are known as exons

humans have about 180,000 exons, consisting about 1.5-2% of the human genome

the human genome has approximately 30 million base-pairs

the second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology

45
Q

What is the diagnostic yield of exome sequencing?

A

its diagnostic yield is about 30-35%