Week 8: Behavioral Genetics and Public Policy

This was the final week of my behavioral genetics course, which was a summing up of the major themes we had learned, and a few examples of how behavioral genetics will intersect with public policy.  Here are the notes:

4 Laws of Behavioral Genetics:

1. All human behavioral traits are heritable.

• For many behavioral traits the strength of heritable influence increases with age.
• Impoverished environments can limit genetic influences on desirable traits, and protective environments can minimize genetic influences on undesirable traits.

2. The shared family environment has minimal impact on individual differences in behavior.

• It doesn't mean that family has no effect on a reared child, but that the family environment affects each child differently.  

3. The non-shared environment exerts a major influence on individual differences in behavior.

• What are the specific effects that matter?
• The "gloomy prospect" - ie, what makes me neurotic is different from what makes you neurotic.  

4. Human behavioral traits are polygenic.

• Effects of any one gene on personality, general cognitive ability, or most complex medical issues are small.  Likely, thousands of genes are contributing.

Genomic Medicine:  What will it take to use genes in medical treatment?
1.  Disease risk can be accurately forecast genetically, preferably prior to disease onset Genetic Prediction

• As it becomes cheaper, more and more people will have their genome sequenced, and we will learn more and more about the genetics of disease.

2.  Prevention/intervention efficacy will differ depending on each individual’s genotype Individualized Medicine (GxE)

• Pharmacogenomics - learning how your individual genes affect the efficacy and toxicity of a particular drug on you.  

3. Individuals will want to know their risk status and once known be willing to take preventive action Genetic Counseling/Behavioral Medicine

• What are the psychological consequences of a positive test result (especially for diseases where there is currently no treatment)?  
• Many individuals who are known to be at risk choose not to get tested.  

Genomics and the Law

• We tend to attribute less personal responsibility when phenotypes are highly heritable, and more personal responsibility when behaviors are not as attributable to genetics.
• Emphasis on choice - defendants don't choose to have genes with a greater vulnerability to aggressive or impulsive behavior, the same way that defendants don't choose to be abused as children.  

Week 7: Genes, Environment, and Development

This is the 7th week of my Behavioral Genetics class, and we are also right in the middle of moving, so this week's notes are even rougher than usual.  Here are things I hope to remember about genes and development:  

Evidence for existence of shared and nonshared effects

 • Schizophrenia – Predominant source of environmental influence appears to be non-shared

 • General Cognitive Ability – Predominant source of environmental influence appears to be shared 

• In general – Predominant source of environmental influence appears to be non-shared 

There are, however, some behavioral traits that show a shared environmental effect (this might be because these are the domains that parents focus on when they rear):

• General cognitive ability 

• Antisocial and rule-breaking behavior 

• Social attitudes including religiousness

Liberal v. conservative:  no heritable effect, all environment - until age 20, then there is suddenly heritability in political leanings.  

(For those traits that show shared environmental influence (e.g., GCA, social attitudes, and rulebreaking) the strength of that influence declines markedly once relatives move apart.)

For general cognitive ability, genetic influence increases with age.  (This is interesting because you would expect it to be the opposite - that environmental influence would increase with age as more life experiences pile up.)  Why is this?  as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

Gene Environment Correlation:  Statistical correlation between the magnitude of genetic effect and the magnitude of environmental effect

3 types of Gene Environment Correlation:

1.  Passive - Parents who transmit genes that promote the development of a specific trait are likely to also create a rearing environment that fosters the development of that trait  (eg high ability)

2.  Reactive - Our experiences are in part a function of the reactions our behaviors elicit from others and to the extent our behavior is genetically influenced, this induces a G-E correlation  (eg, fussy baby elicits a different reaction than a happy baby)

3.  Active - Our experiences are in part a function of the choices we make based upon our abilities and interests. And to the extent our abilities and interests are genetically influenced, this will induce a G-E correlation  (for example, choosing to go to the library and study v. going to the bar to drink)

Parent behavior is related to offspring functioning.  Is this environmentally causal or genetic?

Example:  overprotective parents have anxious kids.  (It's possible that parents are overprotective because they are anxious, and their anxiety was genetically passed down to kids - so not environmentally caused.)  (Also possible that it's reactive - anxiety in the child elicits overprotectiveness in the child.)

Robust association between mother smoking during pregnancy and ADHD.  Is this causal?

- Mothers who smoke may have other things in common with each other, and that other thing is common is actually the thing that increases the risk of ADHD.  

- Effective way to test this is sibship design...in this example, mom smokes during first pregnancy but not second.  You find enough of this circumstance and run the numbers.  

Unit 6: Intelligence

This week's class focused on the genetics of intelligence.  This unit was very interesting to me because Joshua's deletion (and most chromosomal deletions where the child is missing millions of bases) can potentially have some effect on cognitive ability.  It was encouraging to learn that intelligence is one of the main areas where environment, and not just genes, can play a big role.  Here are the notes from this week's class:

Definition of Intelligence -

• to understand and use complex ideas
• to adapt effectively to the environment
• to learn from experience
• to engage in abstract reasoning

Is intelligence one thing or many things (and what should be emphasized)?

• Verbal ability
• Numerical ability
• Spacial ability
• Mechanical ability

How does your performance in one area predict your peformance on other types of abilities?

• Could be positively associated, negatively associated, or unrelated.
• Performance on multiple ability tests are always positively correlated, so it implies something common across the 4 tests - your General Cognitive Ability.  
• "General Cognitive Ability" - general intelligence - your performance across the 4
• The absence of perfect correlation does show that they are distinct abilities.

IQ Test

• IQ test samples your skills in multiple intellectual domains and summarizes it in a  number.  
• IQ is a measure of general cognitive ability.  
• Average IQ is 100.  2/3rds of population fall between 85-115.  2.5% below 70, 2.3% above 130.  

What do twin & adoption studies show about the contribution of genetics and environment to intelligence?

• Genetics:  50% heritable
• Shared environment:  35%
• Non-shared environment:  15%
• So, both genetics and environment play an important part in intelligence.  

Gene Environment Interplay

• Average IQs in population have increased 3-5 points per decade in the last several decades.
• Better public health, better public schools
• Adoption studies show that children who were adopted (v. siblings who were not) tend to score much higher in both IQ and school achievement.
• Adoption in general (not just compared to biological siblings) is correlated with higher IQ and higher school achievement, because in general it means a shift to a more advantaged home.
• This is true in working, middle, and professional class homes - but greater benefits as the socioeconomic class goes up.  
• Heritability of GCA is diminished in poor and working class homes.
• This is because in wealthier homes, kids get opportunities which allow them to fully realize their genetic potential; in less wealthy homes, kids don't get these same opportunities and therefore do not always realize their full genetic potential.

Genetic Factors

• Total brain volume is highly heritable.
• Total brain volume is associated with GCA, but probably not the best way to measure GCA.
• Common genetic factors contribute to brain volume and GCA.
• Researchers have not had much success yet in identifying which genes are most highly associated with GCA.  
• Using a genome wide study, they found places on Chromosome 1, 2, and 6, that were correlated with how far students went in school - but extremely small effects.  (consistent with schizophrenia, height, etc.)

Genetics of Intellectual Disability

• What is intellectual disability?
• IQ less than 70. AND
• Deficit in intellectual functioning results in impairments in adaptive functioning AND
• Onset in child
• Implications of the non-normal distribution of IQ
• More individuals with intellectual disability than we would expect with normal distribution.
• 90% of individuals with intellectual disability have mild disability - can live independently but require some assistance; 
• There's 6x greater population of moderate intellectual disability than we would expect, and 6,000x greater population of profound intellectual disability than we would expect.
• Two groups
• Single major trauma - can be genetic, perinatal trauma, etc. (5-10% of all individuals with intellectual disability)
• Due to cumulative impact of many small factors (90-95%, usually the more mild disability, this is who would be expected on the bell curve)
• Males are at higher risk for intellectual disability than females
• 40-50% more likely
• X-linked intellectual disability is a major factor
• Males only have one X chromosome so only require one hit; since females have two X chromosomes, would need two mutations to be affected.  
• Secondly, males are biologically more vulnerable than females - eg, higher mortality rate at all ages, more vulnerable to consequences of low birth weight and birth trauma, higher risk for most neurodevelopmental disorders.  
• Study found that females with intellectual disability have a higher load of genetic risk factors than males affected with intellectual disability.  

Unit 5: Schizophrenia

This week, my Behavioral Genetics class focused on Schizophrenia as an example of how behavioral genetics explains a particular phenotype.  Here are the notes I would like to remember from this week.  Also, below this week's notes is a question I asked in (virtual) Office Hours and the professor's response:

Characteristics of Schizophrenia:

• Positive Symptoms (presence of something that is not normally there):  Thought disorder, delusions, hallucinations, movement disorder
• Negative symptoms (disruption in normal behaviors or emotional response):  Inappropriate affect, deterioration of social behavior, 
• Cognitive symptoms:  Impairments in working memory, attention, executive function
• Tends to start in late adolescence or early adulthood.

Epidemiology of Schizophrenia

• Males are at greater risk for all neurodevelopmental disorders, including schizophrenia.  
• Correlation with lower social classes (but not necessarily causation).
• Frequency of schizophrenia is similar across different countries and ethnic groups - but immigrants have higher rates of schizophrenia than non-immigrants.  
• Reduction in fertility

Twin Studies tell us about:  

1) Genetics of Schizophrenia

• Rare event to find twins (2% of population) with schizophrenia (1% of population).  
• Genetically identical twins are usually less than 50% concordant for schizophrenia - if one twin has it, it's (close to but) less than half the time that the identical twin also has it.
• They show that there is a genetic component, but that environmental factors also important.  
• Risk of schizophrenia increases exponentially with degree of genetic relatedness.  (Not just a linear increase, like in autosomal dominant diseases.)
• Exponential tells you that it must be multiple genes causing schizophrenia.  
• Seems to be between 60-80% heritable.  

2) Environmental Factors Related to Schizophrenia

• Shared environmental influence doesn't seem to be very important:  majority of schizophrenics do not have siblings with schizophrenia, being reared by an adoptive parent with schizophrenia does not increase risk of schizophrenia
• Non-Shared:  MZ concordance is around 50%.  Individuals with schizophrenia have larger ventricles.  Low birth weight, obstetrical complications, maternal conditions (such as malnutrition or flu).  

Identifying Schizophrenia Risk Alleles

1.  The Positional Cloning Strategy

- When you know a trait is heritable, find the position on the chromosome, then identify the genes on the chromosome.  This works well for traits that are caused by a single gene, but not so well for traits that are caused by multiple genes.  

-Candidate gene studies:  target specific genomic regions when looking for association.

-Leading study on this came up with no significant findings.  

2. The GWAS (Genome Wide Association Stragegy)

- The association between each SNP and the phenotype is tested using an array.  

- Learn that the effect of any specific variant is small, even if a trait is mostly heritable.

- Identified risk alleles tend to be very common (many of us are carrying some of them, but just not enough to express the phenotype of schizophrenia) - individually, they have small effects - but they implicate certain pathways.

- They have only figured out about 5% of the heritability of schizophrenia.
- This type of study misses rare variants and structural variants such as CNVs

3. Rare Variants and CNVs

- Rare variants:  There are certain disorders that are more likely when father is older.  With age, men produce more mutations in their gametes than women.
- 22.Q.11.2 syndrome given as example of CNV - individuals with this deletion have 20-30% likelihood of having schizophrenia, and 1% of people with schizophrenia have this deletion.
 -Note:  "De novo" means that neither the father nor the mother has the deletion, but somehow in cell reproduction, the child gets part of one of their two chromosomes cut out.  

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Here's the answer to my office hours question from last week:  Why is it that children with the same genetic deletion can have very different phenotypes?  (So for example, in 4q, many but not all kids have heart problems, Pierre Robin Sequence, finger and toe anomalies, etc.  Why wouldn't it be all or none if they have the same set of missing genes?)

1.  It's not always the same exact region that's being deleted - even if you have a matching number on the micro-array, these copy number variants cover millions of bases - so the deletions have significant overlap, but they are not actually exactly the same and there may be significant differences happening at the boundaries.  

2.  If you only have one whole copy of a particular chromosome (and the other contains a deletion), then the allele you have on the copy without the deletion becomes really important.  It gives an opportunity for recessive alleles to be expressed, when they would often be "overruled" by the matching dominant allele.  

3.  Genes at other regions of your genome can be interacting or impacting expression.  

Behavioral Genetics Week 4: The Human Genome

This week in my Behavioral Genetics class, we learned about the Human Genome.  This included several lectures on genetic variation, which was very interesting to me because it's directly pertinent to Joshua's situation.  It's interesting to see (even in a lightning speed flyover on the subject) how far the field of genetics has come in the last 20 years, and how rapidly it's progressing.  The professor said that he expects knowledge of the human genome will revolutionize medicine, which is exciting. Without further ado, things I want to remember about this week's lesson on the Human Genome...

• DNA provides a code for building proteins, chains of amino acids
• DNA (double strand) is transcribed into RNA (single strand), then translated into proteins.

Gene Structure:
1.  There is an orientation:  5' (upstream) to 3' (downstream).
2.  Upstream (5’) is a regulatory region, a promoter that determines which strand of DNA will be used and where the gene starts.
3. Genes are not continuous DNA sequences, they contain introns and exons (Exons – Expressed, contain the protein coding sequence; Introns – Intervening sequences)

3 surprises about the human genome:
1.  Most of the human genome is non-coding (98.5%) (but non-coding does not mean non-functional).
2.  Humans have a small number of protein coding genes. (Humans have around 21,000 genes.  This is slightly more than a fruit fly and slightly less than a mouse.)
3.  Comparative genetics - "we're all essentially identical twins".  All humans share 99.9% of DNA the same as each other.  But think about overall scale - even though we're mostly the same overall, there are still 6.4 million differences.  Very small changes in our DNA can have rather significant effects.

Genetic Variance Among Us

• Insertions / Deletions - small number of bases (less than 100) missing or added - this is very common
• Copy number variants - large segments of DNA (at least 1000 bases) have been deleted or inserted.  Ex:  22q11.2 (missing about 3 million bases) [This is the type of genetic variance that Joshua has.]
• Aneuploidy - having an extra or missing chromosome (ie Down's Syndrome).  These are fairly rare.
• Organization - differences in how DNA is organized - inversions and translocations.

The Unique Case of the X Chromosome

• Women have two X chromosomes.  Men have an X and a Y chromosome.  
• X Chromosome has a lot more protein producing material than Y chromosome. (2,000 v. 80)
• But women do not produce a lot more protein products than men, because in women, only one X chromosome is active - the other becomes inactive.  
• Different cells will have different X chromosomes turned off.  The timing is random, but it happens early in embryonic development, and once it happens it's permanent - when those cells duplicate, the same X will be turned off.   
• This show that there is a mechanism of genetic regulation.  

Prader Williams and Angelman's:  Two Different Genetic Disorders on the Same Part of the Genome

• Prader Williams:  uncontrolled eating, low muscle tone, cognitive dysfunction.  15q11.2
• Angelman's:  movement and language disorder, behavioral (happy).  Also 15q11.2
• Even though these deletions are de novo, in PW it's always the father's chromosome that's deleted.  In Angleman's, it's always the mother's chromosome that had the region deleted.
• Why should it matter if it was father's or mother's chromosome?
• There are regions where whether you inherited from father or mother makes a very big difference in the expression of the gene.  About 1% of our genomes are imprinted this way.
• Another possibility: uniparental disomy - the child ended up with two chromosome 15s from just the mother, or from just the father, rather than one chromosome 15 from each.
• Another example in nature of genes expressing very differently depending on whether they were inherited from the father or the mother:  ligons (father is lion, mother is tiger - they are large) are very different than tigons (father is tiger, mother is lion - they are quite small).

Epigenetics 
Epigenetics is the study of genetic regulation - differences in DNA expression that is not due to difference in the DNA sequence.  3 examples of this:
1.  X chromosome inactivation
  - Occurs early (in first couple weeks of embryonic development)
  - It's stable - once it becomes inactive, it stays that way
2.  Imprinting - some genes only expressed if inherited from mother, some genes only expressed if inherited from father.
  - Once again, it happens early and it's stable.
3.  Gene expression pattern - what differentiates a muscle cell from a liver cell from a blood cell.
  - Again, happens early and it's stable.

Could factors in our environment cause epigenetic effects?
 - Yes.  Some examples:  maternal malnourisment (increased sensitivity in early embryonic development), grooming in a mice study,

Behavioral Genetics Week 3: Heritability

This was week 3 of my Behavioral Genetics class, and this was the first week where (at times) I felt lost.  For Week 3, the professor taught some of the basic vocabulary words of genetics, gave a basic explanation for how heritability is calculated (this is the part where I got lost and I'm not even going to make an attempt to explain or remember it), and introduced the concept of gene environment interaction.  Part One of this blog post is vocabulary that I want to remember, so feel free to scroll on past.  Part Two of this blog post talks about gene-environment interaction, which is more generally interesting.

Part One:  Genetics Vocabulary

• Gene - a functional unit of inheritance
• Allele - alternative forms a gene governing a specific character can take (ie Y and G for color)
• Genotype - the two alleles one inherits
• Homozygotes - YY or GG
• Heterozygotes - YG or GY
• Genes are located on chromosomes, which are located in the nucleus of all our cells.
• Chromosomes 1-22 are autosomes. (Numbered roughly from largest to smallest.)  The third chromosome is the sex chromosome.
• Recombination - exchange of genetic material between homogous chromosomes
• Variance:  an index of the degree to which individuals differ for a quantitative trait 
• Biometrics:  Take a phenotypic variance and find what portion is associated with genetic variance and environmental variance.
• Additive genetic effects - the effect this gene adds does not depend on what genes it pairs with
• Non-additive genetic effects - the effect this gene adds does depends on what genes it pairs with
• Shared Environment - things individuals growing up in the same home share (income level, parents approach to child rearing, neighborhood)
• Non-shared Environment - environmental effects that individuals growing up in the same home do not share (peer group, accidents, differential parental treatment to each sibling

2 different heritability measures:

• Total heritability - indexes the effect of all genetic contributions.
• Additive heritability - measures the effect of additive genetic contributions.

ACE
A = Additive
C = Shared environmental factors
E = Non-shared environmental factors

• A usually explains at least half of traits (moderate to large effect)
• C often doesn't seem to matter (birth weight is an exception, type of religion is also an exception)
• E are always important (moderate effect)

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Part Two:  Gene Environment Interaction

Gene environment interaction:  The magnitude of the genetic effect depends on the environment.  Certain inherited genes are a "vulnerability", but they are only trigger a particular behavior if the person with the vulnerable gene also interacts with a particular type of environment. Here are some examples:

Aggression:  do genetic factors influence level of aggression?
 - If reared in a nurturing, protective home, then NO.
 - If reared in a chaotic, dysfunctional home, then YES.

Depression:  Is there gene environment interaction for depression?
- Depression is heritable and some of the genes for depression are not dependent on experiencing a certain environment.
- But, there are environmental influences that can influence the genetically based level of depression.
- Life stressors trigger the gene environment interaction for depression.
   - If you have low levels of life stress, then NO gene environment interaction.
   -  If you have high levels of life stress, then YES gene environment interaction.

IQ is an example of when there is NOT a gene environment interaction.
- Genes are important to IQ and environment is also important to IQ.
- But there are no genes which influence IQ that are triggered (or not) by experiencing a particular environment.

Why is gene-environment interaction important?
- In gene environment interaction, there are (potentially) two different points where you can intervene to help with problematic phenotypes.
– If you know that someone has an "at risk" gene, you can do environmental interventions to stop the vulnerable gene from being triggered - ie, Increase family cohesion in those at risk for aggression
– If you know that something is caused by a gene (as well as triggered by environment), then there is the possibility of pharmaceutical treatments.

Behavioral Genetics Class Week 2: Twin Studies

This is the summary of Week Two of my Behavioral Genetics class.  This week, the instructor discussed the types of experiments used to investigate genetic and environmental contributions to individual differences:

Twin Studies
- The main type of experiment used is twin studies.
- Twin studies work well because they provide two excellent naturally occuring test groups.  Monozygotic twins ("MZ") share 100% of their DNA and also have a (roughly / arguably) 100% similar upbringing.  Dizygotic twins ("DZ") share 50% of their DNA (like siblings) and have a 100% similar upbringing.  Comparing and contrasting these two groups can help show whether traits are more influenced by genetics or environment.
- Occasionally, MZ twins are reared apart, so in this case they share 100% of their DNA and (again, roughly / arguably) 0% of their upbringing, so all physical and psychological similarities between twins reared apart are due to genetics.
- The findings from twin studies are:
  - MZ twins are almost always more similar than DZ twins, even when reared-apart.
  - For many (but not all!) traits, reared-apart twins are not much less similar than reared-together twins.  (The most notable exceptional trait is IQ, where environment seems to play a bigger role.)
  - MZ twins are never perfectly similar (so, while the first two points show that genetics plays a big role, this shows that environment also plays a role).

Adoption Studies
- A second type of study used is adoption studies.  Psychologists compare adopted siblings (not genetically related, but raised in the same home).  Also, psychologists compare adopted children to their birth parents and also to their adoptive parents.  The findings:
- In the adopted sibling studies:  There is very little similarity in personality (ie emotionality, happiness, etc.) between adopted siblings.  The correlation is not zero, but less than the correlation with twins or biological siblings.
- In the parent studies:  Adopted individuals tend to resemble both sets of parents, but they resemble their birth parents more than their adoptive parents (for psychological traits).

Behavioral Genetics class Week One: Intro

To fulfill one of my New Year's resolutions, I'm taking a Coursera class.  Coursera is a website that offers free online college classes in a wide variety of subjects.  I am taking an introductory course in Behavioral Genetics.  I find this subject inherently interesting - I was a psychology major in college - but the main reason I'm taking it is to get some framework for thinking about things with Joshua.  Specifically:

• What kind of  behavioral / personality / cognitive traits are caused by his missing genes (nature)
• What environmental (nurture) interventions can we do to try to help in areas that are more difficult for him. 

I don't expect that this course will speak directly to Joshua's situation, but I'm hoping that it will give me an understanding of the basic concepts in behavioral genetics so that I will have a better idea what I'm doing when I try to research 4Q deletions.

So I'm going to try to do a blog post each week writing about any interesting and helpful things I learn from the course.  This will mostly be for my own memory so I'm not going to put these up on Facebook, but I will put them on my blog so that people can follow along if they're interested.  This is not an attempt to summarize the whole course - it's free and easy to sign up - but just things that I want to remember.
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Week One was an introduction to the field of behavioral genetics.  Points of interest:

• At the beginning of the twentieth century, there was a widespread belief that everything about a person - their personality, intelligence, behavior, etc. - is determined by their genes.  This led to the Eugenics movement, which was an effort to improve human society by influencing who does and does not reproduce.  I read a lot about Eugenics in college, in both my history and psychology classes.  But now that I have a child with a chromosome disorder, it was physically painful to hear a lecture about forced sterilization, "three generations of imbeciles is enough", etc.  Also made me grateful for how far we as a society have come in tolerance towards individuals with differences, even though there's plenty of work to be done towards inclusion.
• In the 1960s, the popular idea was that humans are born as "blank slates" and everything about us is formed by our environment.  The most radical "proof" of this idea was the John / Jane Doe study.  There were two identical twin boys; one was (tragically) accidentally castrated at age one.  Psychologists advised the parents to raise this boy as a girl.  This appeared to go well for the first ten years, and the psychologist published papers stating that this proved the truth of the blank slate theory.  But once "Jane" reached puberty, she started having serious suicidal ideation, so her parents revealed the truth, and she immediately changed her name and gender identity back to male.  (And continued to have psychological trouble for the rest of his life.)  There are so many crazy, where-was-the-ethics-board issues in this story that it would be hard to use it to prove anything -- but it does offer evidence pure "blank slate" theory is an oversimplification.  
• So now psychologists believe that people's behavior, personality, and cognition is a mix of nature and nurture.  Behavioral genetics uses genetics methodologies to study the nature and origins of individual differences in human behavior.
• Pleiotropy - genes can have multiple phenotypic effects (Phenotypic = that which is expressed or observed, such as behaviors and symptoms) (Genotypic = that which is inherited)
• Gene-environment interaction - Genetic effects depend on environmental context.
• PKU - example of inborn error of metabolism.  Children born with one missing gene exhibited all sorts of serious symptoms.  The gene produced an enzyme that helped the body do several different things.  Once the missing gene was identified, the problem could be corrected relatively easily  with a change in diet.  If the problem was not identified early in childhood, it led to severe problems for the rest of the child's life.  This is not the case with every missing gene (that it will lead to such serious problems, but can also be easily treated) -- but it does remind me that I would like to get Joshua a consult with a metabolic doctor if we get a chance.