#5 Neurodevelopmental Genetics

Question 1

Who are the 5 people who contributed to the landmarks of genetics?

Answer 1

Mendel, Garrod, Avery/McCarty/Macleod, Watson and Crick, Sanger

Question 2

What were the contributions made by Mendel and Garrod to genetics?

Answer 2

Mendel: did his pea plant experiments from 1856-1863 and established new laws of heredity called the Laws of Mendelian Inheritance
Garrod: physician, was the first to connect human disorder to mendel’s laws of inheritance, and proposed the idea that diseases come about through a metabolic route leading to the molecular basis of inheritance

Question 3

What were the contributions of Avery, McCarty, Macleod and that of Watson and Crick?

Answer 3

A/M/M: discovered that DNA is our hereditary material, and that it can change the products of cells, and also clarified the chemical nature of gases
Watson and Crick discovered the twisted ladder structure of DNA, and provided insights into the genetic code and protein synthesis, as well as understood how genes control chemical processes within cells

Question 4

What was the contribution of Sanger to genetics?

Answer 4

He made DNA sequencing methods (1977), and determines the amino acid sequence of insulin and numerous other proteins, made the foundational discovery for the central dogma of molecular bio, it was the first genetic test used, BUT you need to know the disease and have an idea of what gene causes it, because you can only sequence one gene at a time

Question 5

What is the Human Genome Project?

Answer 5

Happened from 1990-2003 and it was an international research initiative to sequence the human genome, used over 20 uni/research facilities to make it happen in UK/USA/France/Germany/ Japan/ China.
They generated the first sequence of the human genome, produced a sequence that accounted for 92% of all human genome, there is 20,500 genes in each human, only 6000-7000 of them we know are disease causing, and all locations of genes in the human genome are known

Question 6

What are 4 important genetic discoveries following the completion of the Human Genome Project?

Answer 6

1987: Collins and Tsui find gene that contains the variants that cause cystic fibrosis
1990: BRCA 1 gene is found
2010: First drug to treat subset of s=cystic fibrosis patients is approved by the FDA
2020a: health canada approves Zolgensma which is a one time drug gene therapy treat pediatric patients with spinal muscular atrophy (usually do not live long)

Question 7

How many kBP are in the nuclear genome?

Answer 7

3,000,000 and most genetic tests are done here

Question 8

How big is the mitochondrial genome? How is it different from the nuclear genome?

Answer 8

Less than 17 kbp, maternally inherited, encodes 13 subunits of enzymes involved in oxidative phosphorylation, ribosomal RNA, and transfer RNA required for translating transcripts of mitochondrially encoded peptides, encodes subunits of the electron transport chain
About 100 rearrangements or missense variants in mtDNA cause human disease

Question 9

What are the four things that are important to know when conducting genetic tests?

Answer 9

1. Terminology: allele, variant, wild-type, homoz, heteroz
2. Variant classification: can be pathogenic, likely pathogenic, variant of unknown significance (VUS), likely benign, benign
3. Genotype and phenotype
4. Pedigree: familial picture to map inheritance of diseases through a family

Question 10

What are the 5 types of traditional mendelian inheritance?

Answer 10

1. Autosomal recessive
2. Autosomal dominant
3. X-linked recessive
4. X-linked dominant
5. Y-linked

Question 11

What are autosomal recessive and dominant inheritance? What is de novo?

Answer 11

1. Autosomal recessive: two pathogenic variants, inherited from healthy carrier parents, 25% chance of being affected
2. Autosomal dominant: one pathogenic variant, inherited from affected parent, account for more than 50% of known mendelian disorders
3. De novo: subset of autosomal dominant, where neither parent is affected but due to a mutation in their sperm/egg the offspring inherits a mutated dominant allele

Question 12

What are x-linked recessive and x-linked dominant inheritance?

Answer 12

1. X-linked recessive: if the father is affected, all daughter will be too, if mother is a carrier then male offspring that have the gene will be affected and daughters will be carriers
2. X-linked dominant: affected fathers mean affected daughters, affected mothers could lead to affected sons or daughters

Question 13

What are the two non-traditional mendelian inheritance patterns?

Answer 13

Mitochondrial inherited
Complex/multifactorial inheritance such as genomic imprinting and unstable repeat expansions

Question 14

What is mitochondrial inheritance?

Answer 14

Affected fathers will not pass on their disease to any offspring, and affected mothers will always have effected children and show different phenotypes

Question 15

What are other etiological factors causing neurodevelopmental disorders? NOT ALWAYS HAVE A GENETIC CAUSE

Answer 15

Trauma, nutritional factors, hypo-ischemic injury, toxic exposure, infections, immunologic factors, aging/maturation, iatrogenic disorders, oncological disorders, and GENETICS

Question 16

What are the implication of a genetic diagnosis in neurodevelopmental disorders? (7)

Answer 16

Prognosis, ongoing medical management, assessment of recurrent risk, surveillance for complications, implementation of prevention programs, limiting unnecessary testing, access to research treatment protocols

Question 17

What are the 6 genetic tests used in clinical practice in developmental disorders?

Answer 17

Karyotype
Chromosomal microarray
Single gene panel
Muti-gene panel
Exome sequencing
Genome sequencing

Question 18

What is involved in a karyotype test?

Answer 18

Make a map and visualize all the chromosomes, can only see BIG duplications/insertions or deletions of chromosomes, it was the first genetic test

Question 19

What is involved in a chromosomal microarray?

Answer 19

Broad, non-specific genetic tests to detect large insertions or deletions of DNA, cannot see anything less than 300 kbp long, it is the first tier test for kids and adults with neurodevelopmental disorders.
You combine reference DNA with test DNA, label it, hybridize it to the microarray and then can see the deletions or insertions
Diagnostic yield is 10% therefore not a very reliable test, does not give a diagnosis very often

Question 20

What is involved in a single gene panel?

Answer 20

Sanger sequencing, need and idea of what the disease is and the gene that causes it in order to use it

Question 21

What is involved in a multi-gene panel?

Answer 21

Looking at one disorder caused by multiple genes, based on phenotypes, looks at all the chosen genes at once
Ex. The multi-gene panel for epilepsy is 450 genes
Has diagnostic yield of 20%

Question 22

What is involved in exome sequencing?

Answer 22

Sequences only the exons (protein coding regions) of the genome, but it takes 6 months to get results and is the most costly.
The first step is to select only the exons from the genome, then sequence it using any high-through-put DNA sequencing tech
It identifies single nucleotide variants (SNV) and small indels and has a diagnostic yield of 30-35%

Question 23

What is involved in genome sequencing?

Answer 23

Sequences both introns and exons

Question 24

What was the result of CASE 1? (15 YO female, normal milestone, nonverbal intellectual disability, not social but NO autism)

Answer 24

Used a MECP2 genetic test and found a missense mutation and thus she has RETT syndrome

Question 25

What was the outcome of CASE 2? (6MO boy, fever and seizures)

Answer 25

Underwent multi-gene panel, and found that he has pyroxidine dependent epilepsy, and once put on pyroxidine and protein restricted diet he was fine?
(2 pathogenic variants in the ALDH7A1 gene)