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Branching Off The Tree

For anyone who has read Far from the Tree by Andrew Solomon, you know that his premise is that diversity is what unites us all. He explains that individuals from different families who have the same type of trait or condition are often more like each other than the families they come from, hence the title of the book. He writes, among other things, about individuals and families with deafness, dwarfism, Down syndrome, autism, schizophrenia, multiple severe disabilities, prodigies, and those who are transgender. He posits that although each of these situations or conditions could potentially be isolating, the experience of difference within families is universal. If you have not read this incredible book, please do yourself a favor and read it. It's very long, but each chapter stands on its own, and you can read any that are of interest to you and skip the others. And just a warning - this blog post is also long in response!

Mr. Solomon was the keynote speaker at the Annual Conference of the National Society of Genetic Counselors (NSGC) several years ago, and I was lucky enough not only to hear him speak about this work, but also to meet him briefly at a book-signing. He was friendly, gracious, and incredibly articulate. I tell people it helps to have a thesaurus handy when you read or listen to his work. What I thought would be interesting to do here is address the known genetics of the conditions Mr. Solomon addresses in his book.

Deafness has many known genetic and environmental causes, and of course many that are not known. Genetics accounts for minimally half of all cases of profound congenital deafness; analysis of any other clinical features can help to determine whether the individual's deafness may be isolated or syndromic. It may surprise you that over 120 genes for deafness have been identified. Alterations in one gene in particular, called Connexin 26, account for greater than half of all genetic cases in some populations. Most cases of genetic deafness result from variations of a single gene, but in some, recessive variations of two (or more) genes are actually involved.

We each have approximately 20,000 genes in each cell, and we have two copies of each of these, one from each parent. A recessive condition is one where both copies have to be altered in order for the individual to be affected. So therefore, both parents must be carriers, having one normal copy and one with an alteration, and both parents pass on the altered copy to their child. Of course when more than one gene is involved, the genetic evaluation and counseling can be a bit more complicated. As you might imagine, a specific genetic diagnosis can sometimes be of great clinical importance, as there may be other conditions also present in the affected individual. In some cases, genetics can provide empowering knowledge that may allow deaf couples to know whether their children will be hearing or deaf before they are born, or even potentially before they are conceived.

Genetics accounts for minimally half of all cases of profound congenital deafness; analysis of any other clinical features can help to determine whether the individual's deafness may be isolated or syndromic.

Janice Berliner, 2019

Dwarfism is a condition of short stature, defined as an adult height of 4 feet 10 inches or under, as a result of a medical or genetic condition. The average height of an adult with dwarfism is 4 feet. It can be caused by any of more than 200 conditions; the most common types, known as skeletal dysplasias, are genetic. These involve abnormal bone growth that cause disproportionate dwarfism, where either the trunk is of average size but the limbs are shortened, or where the trunk is shortened but the limbs are of average size. Examples of skeletal dysplasia are achondroplasia, spondyloepiphyseal dysplasia, and diastrophic dysplasia. These are all rare conditions, caused by genetic mutations that can occur spontaneously or be inherited. Diastrophic dysplasia and most spondyloepiphyseal dysplasias are inherited in a recessive manner, as described above. This means that the parents of the affected individual will not be affected, each of them only having one copy.

Achondroplasia is inherited in a dominant manner, meaning that only one copy of the gene pair needs to be altered, so it only needs to be inherited from one parent. However, an interesting feature of achondroplasia is that often the parents of affected children do not carry the mutation themselves and are not affected; this can happen if an alteration occurs in the embryonic DNA mutation at the time of conception. Because this is a one-time event, other children of the same couple are extremely unlikely to be similarly affected.

Down syndrome occurs when an individual has an extra chromosome number 21. For this, you might need a little background. Chromosomes are the structures in all of our cells that contain our genes. There are 23 pairs of chromosomes, the first 22 being called autosomes, and the last pair called the sex chromosomes, X and Y. A person with one X and one Y will be male (at least genetically) and a person with two XXs will be female (same disclaimer). There can be situations where a person has more than two sex chromosomes, but this is a discussion for another blog post! When someone has 47 chromosomes instead of 46, and the extra is a number 21, then that person has Down syndrome. In rare cases it can be inherited from a parent who has what's called a chromosome translocation, but the vast majority are sporadic, spontaneous occurrences the happen prior to conception in the process of chromosome replication and division in either sperm or egg cell. The common notion of Down syndrome is that it only happens to older mothers, but there are a couple of things to know about this:

1. While it is true that the risk for this type of occurrence goes up as women age, older pregnant women are also far more likely to pursue prenatal testing and rule out Down syndrome in pregnancy. The choice is theirs whether to continue the pregnancy, and since many do not, the overall percentage of children with Down syndrome being raised by older parents is actually lower than you might think.
2. Down syndrome is only one type of chromosome disorder that occurs more frequently with advancing maternal age. There are others, typically more severe, that can also be ruled out with certain prenatal genetic tests.

Approximately 50 to 90% of autism is hereditary, such that genetic factors are critical to its development.

Janice Berliner, 2019

Autism spectrum disorder (ASD) is a group of early onset neurodevelopmental disorders, characterized by impaired social and communication skills and stereotypical behavior. The actual symptoms can range from severe intellectual disability (ID) and very poor adaptive behavior skills, to average or even exceptional IQ and the ability to live an independent life. Approximately 50 to 90% of autism is hereditary, such that genetic factors are critical to its development. However, environmental factors, such as infections or the use of certain drugs during pregnancy, are thought to play a role as well. Despite many theories to the contrary, there is no evidence that vaccines play any role in the development of ASD.

ASD can result from many different underlying genetic variants, which can make recurrence risks in a family very difficult to predict. A polygenic (many genes) or multifactoral (genes plus environmental factors) model used to be considered the inheritance patterns accounting for most cases of ASD. However, a considerable number of individuals with ASD have been found to have rare mutations that cause a damaging effect on neuronal development and may well be sufficient to cause the disorder without environmental influences. Much of our knowledge comes from studies that have identified gene variants with moderate to high risk, and it is estimated that variants in more than 400 genes can account for ASD. Rather importantly, none of these genetic alterations individually accounts for more than 1% of the total cases of ASD.

Schizophrenia is a chronic and severe psychiatric disorder that affects how a person thinks, feels, and behaves, and those with schizophrenia may seem like they have lost touch with reality. Although this disorder is not as common as other psychiatric illnesses, the symptoms can be quite serious. It is not uncommon for a family to have individuals with schizophrenia, bipolar disorder, clinical depression, eating disorders, addiction, and/or other conditions. Typically, psychiatric disorders do not follow the simple rules of Mendel's laws of inheritance. And although the full picture is not yet known, it is clear that they arise as a result of both genetic and environmental factors. For more details, please see my previous blog post on the genetics of psychiatric illness for more information about this (janiceberliner.com).

Multiple severe disabilities is how Andrew Solomon describes it. In genetics we tend to say multiple congenital anomalies. Either way, we're talking about a situation in which an individual is born with several distinct conditions going on simultaneously. This can happen for many reasons. In some cases, the person has a chromosome abnormality (described above) such that all or many of the genes that reside along that chromosome are disrupted, mutated, or inactivated. Naturally, this can cause many different disorders that occur together. Likewise, there are what are called contiguous gene syndromes, in which the deletion of a piece of a chromosome removes one copy of several genes at once, each causing a separate disorder, condition, or birth defect. Finally, there may simply be one syndrome, caused by one gene mutation, that can result in multiple conditions. Intellectual disability of varying degrees is often present in the situations described here. When a child is developing slowly and/or has multiple congenital anomalies, the suggestion is to be evaluated by a pediatric geneticist and genetic counselor in an attempt to figure out the underlying cause. This has the advantage of providing a reason to desperate parents, perhaps some therapy for the child, and information regarding recurrence risks for future pregnancies or family members.

Prodigies are children who show an early and exceptional adoption of what are typically thought of as adult abilities. The child prodigy is a precocious specialist in a particular field of endeavor. Music is the most common (as described by Mr. Solomon), followed by chess, mathematics and, to a much lesser extent, visual art. It has sometimes been asserted that prodigies are simply the result of high intelligence combined with intensive training in a particular subject at an early age. But interestingly, while prodigies generally demonstrate at least a moderately elevated level of intelligence, their full scale IQ scores are not consistently on the extreme end of the spectrum. What tends to be extraordinary, however, is the child's working memory scores. Additionally, there is now a known connection between child prodigies and autism, as prodigies' family histories often show a statistically unlikely number of autistic relatives. This is on top of the fact that child prodigies tend to have elevated Autistic Quotient (AQ) scores with respect to attention to detail.

While general intelligence is heritable to a fair degree, high ability in a specific field is also required for a child to be considered a prodigy. In other words, children with a high IQ are many, prodigies are few. Whether children can possess innate inherited talent has been much debated. Even with such family histories where, for example, the musical prodigy comes from a family with substantial musical background, it is difficult to disentangle the genetic and environmental contributions since the family would provide very favorable conditions to excel in music. However, twin studies have shown that both musical ability and mathematical achievement have a substantial genetic component. Suffice it to say that the data isn't all there, but prodigies are likely the result of genes for intelligence and unusually good memory, coupled with an environment that encourages the child to utilize his or her skills to excel.

Transgender: The modern concept of gender identity is probably still developing. The American Psychological Association defines gender identity as, "a person's deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender, such as genderqueer, gender nonconforming, or gender neutral. These may or may not correspond to a person's assigned sex at birth or primary or secondary sex characteristics. Gender identity is complex, multifactorial, and polygenic, meaning that many genetic factors likely contribute to the development of gender identity through complex interactions with each other, as well as non-genetic factors such as environmental influences. With luck, the available research can be used to reduce stigma for those who are transgender.

If these topics are of interest to you, I really encourage you to check out Far from the Tree. And as always, to find a genetic counselor in your area, go to NSGC.org and click on "find a counselor."

The Genetics of Some Common Conditions
The Importance Of Knowing Your Family History

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