Lecture 5: Developmental Genetics of the Human Brain

Question 1

When does the development of neurons occur?

Answer 1

the first and second trimester

Question 2

When does the development of astrocytes and oligodendrocytes?

Answer 2

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

Question 3

When are the first neuronal circuits established?

Answer 3

established in the embryo shortly after neurons are born

Question 4

When are cerebral cortical areas established?

Answer 4

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

Question 5

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

Answer 5

it is slow

Question 6

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

Answer 6

motor skills
cognition
communication
behavior

Question 7

What are some examples of neurodevelopmental disorders?

Answer 7

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

Question 8

What are etiological factors causing neurodevelopmental disorders?

Answer 8

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)

Question 9

What are some examples of developmental domains?

Answer 9

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

Question 10

What is global developmental delay?

Answer 10

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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

What are the implications of etiologic determination?

Answer 13

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

Question 14

What is inheritance?

Answer 14

genetic information is passed on from parent to child

Question 15

What is the Human Genome Project (HGP)?

Answer 15

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

Question 16

What is genotype?

Answer 16

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

Question 17

What is phenotype?

Answer 17

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

Question 18

What does allele mean?

Answer 18

an alternate form of a gene

Question 19

What does wild-type mean?

Answer 19

an allele in its most common form in a population

Question 20

What does variant mean?

Answer 20

an allele that has a permanent alteration in its DNA sequence

called a mutation in old terminology

Question 21

What does homozygous mean?

Answer 21

two identical alleles

Question 22

What does heterozygous mean?

Answer 22

a single allele for a gene

Question 23

What is the terminology for variant classification?

Answer 23

pathogenic

likely pathogenic

VUS

likely benign

benign

Question 24

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

Answer 24

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

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

Question 25

What are traditional Mendelian inheritance patterns?

Answer 25

autosomal recessive

autosomal dominant

X-linked recessive

X-linked dominant

Y-linked

Question 26

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

Answer 26

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

mitochondrial inheritance

Question 27

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

Answer 27

1/4 children will be affected (AA)

2/4 children will be carriers (Aa)

1/4 children will be unaffected (aa)

Question 28

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

Answer 28

2/4 children are affected (Aa)

2/4 children are unaffected (aa)

Question 29

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

Answer 29

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

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

Question 30

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

Answer 30

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)

Question 31

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

Answer 31

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

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

Question 32

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)?

Answer 32

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)

Question 33

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

Answer 33

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

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

Question 34

What is the importance of genetic testing?

Answer 34

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

Question 35

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

Answer 35

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

Question 36

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

Answer 36

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

Question 37

What is traditional genetic testing?

Answer 37

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

Question 38

What is chromosomal microarray?

Answer 38

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%)

Question 39

What is diagnostic yield of chromosomal microarray in ID?

Answer 39

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

11.1% diagnostic yield in non-syndromic developmental delay

Question 40

What is next generation sequencing (NGS)?

Answer 40

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

Question 41

What are the advantages of genomic testing?

Answer 41

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

Question 42

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

Answer 42

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

Question 43

What is exome sequencing (ES)?

Answer 43

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

Question 44

What are the two steps of exome sequencing?

Answer 44

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

Question 45

What is the diagnostic yield of exome sequencing?

Answer 45

its diagnostic yield is about 30-35%