Familial hypospadias

Inheritance

What is X-linked recessive inheritance in hypospadias?

Chromosomes are the structures that hold all of our genetic information. Our genetic information is encoded as genes, which are individual instructions for our bodies to grow and develop. Chromosomes come in pairs, one that was inherited from mom and one that was inherited from dad, and therefore the genes that they hold also come in pairs. The first 22 pairs in humans are numbered roughly by size, and the 23rd pair, the sex chromosomes, determine sex (XX for female, XY for male). The word X-linked means that the gene associated with a particular disease is located on the X chromosome.

In X-linked recessive conditions, there is a mutation on a gene on the X chromosome. Females generally show no or milder symptoms because they have a second X chromosome with a normal gene to compensate for the gene with the mutation, and are usually considered carriers. Males only have one copy of the gene, as the gene is not found on the Y chromosome. As a result, if males have a mutation in that gene, they will show symptoms of the condition. Since hypospadias is a birth defect that only affects males, females carriers will never show symptoms. However, for each pregnancy of a female carrier, there a 25% chance of each of the following possibilities:

1. A baby girl that inherits that mutations and is therefore a carrier with no symptoms.

2. A baby boy that inherits that mutation and develops hypospadias.

3. A baby girl that does not inherit the mutation, is therefore not a carrier, and cannot pass down the mutation.

4. A baby boy that does not inherit the mutation and does not develop hypospadias.

For a male with X-linked recessive hypospadias, all of his future daughters will inherit his X chromosome with the mutation and be female carriers of hypospadias. All of his future sons will inherit his Y chromosome, which does not have the mutation, and they will therefore not develop hypospadias and cannot pass it down to their future children.

References
  • http://ghr.nlm.nih.gov/glossary=autosomaldominant
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More Inheritance Content

How is familial hypospadias inherited?

What is autosomal recessive inheritance in hypospadias?

What does autosomal dominant inheritance in hypospadias mean?

What is variable expression in hypospadias?

What is reduced penetrance in familial hypospadias?

I was born with hypospadias, what are the chances that my son will also be born with hypospadias?

We have already had one child who had hypospadias, what are the chances that are next son will also have hypospadias?

How is familial hypospadias inherited?

It is important to remember that scientists believe hypospadias is caused by a combination of both genetic and environmental factors. This is called multifactorial inheritance, in which cases having close relative(s) with hypospadias increases the chance of another baby boy being born with hypospadias in the family. In most cases, there is nothing a parent could have done or could have not done to prevent it. That being said, in rare cases, a genetic change, such as one in the MAMLD1 gene, or changes in a group of genes may play a larger role in causing hypospadias and increase the chance for a baby to have familial hypospadias.

If there is a strong genetic cause for hypospadias, it may run in families in an X-linked recessive, autosomal dominant, or autosomal recessive inheritance. X-linked recessive inheritance means that the genetic condition is linked to a gene on the X chromosome, one of the sex chromosomes. As a result, only males are affected, or more severely affected than females, when one genetic change or mutation is present. Autosomal genetic conditions are not linked to the sex chromosomes. Autosomal recessive inheritance means that an individual has to inherit a mutation on each of their two copies of a specific gene, one from each parent, in order to show symptoms of the disease or condition. Autosomal dominant inheritance means that an individual needs to inherit a mutation on only one copy of a specific gene in order to show symptoms of the disease or condition.

In any of these cases, not everyone who inherits one or two mutations will have hypospadias. This is because of variable expression and incomplete penetrance. With hypospadias, variable expression means that the type and severity of the hypospadias can be different between different people, even in the same family. Reduced penetrance means that not every person who has the necessary mutation or mutations will show symptoms. This can make it different to predict whether a baby boy will have hypospadias and the severity or type of the hypospadias in a family with familial hypospadias.

References
  • http://www.ncbi.nlm.nih.gov/pubmed/15543478
  • Utsch, B., N. Albers, and M. Ludwig. "Genetic and molecular aspects of hypospadias." European journal of pediatric surgery: official journal of Austrian Association of Pediatric Surgery...[et al]= Zeitschrift fur Kinderchirurgie 14.5 (2004): 297-302.
What is autosomal recessive inheritance in hypospadias?

Chromosomes are the structures that hold all of our genetic information. Our genetic information is encoded as genes, which are individual instructions for our bodies to grow and develop. Chromosomes come in pairs, one that was inherited from mom and one that was inherited from dad, and therefore the genes that they hold also come in pairs. The first 22 pairs in humans are numbered roughly by size, and the 23rd pair, the sex chromosomes, determine sex (XX for female, XY for male). The word autosome describes any one of the numbered, non-sex chromosomes. In terms of inheritance, this means that the gene associated with a genetic condition is located on one of these non-sex chromosomes.

Autosomal recessive inheritance means that an individual needs to have a mutation on both copies of the gene in order to show symptoms of the condition. Typically, this means that an individual inherited a mutation from each of their parents. Each of their parents therefore has a mutation on one of their two copies of the gene while the other copy of the gene is normal. Each parent would therefore be considered a carrier of the condition, and carriers do not show any signs or symptoms of the condition.

In a family where both parents are carriers for autosomal recessive hypospadias, there is a 25% chance with each pregnancy for both parents to pass down the mutation to the baby. However, only baby boys will develop hypospadias. There is also a 50% chance that only either the mom or the dad passes down the mutation, in which case the child is also a carrier and will not develop hypospadias. If that child's future partner is also a carrier of a mutation in the same gene, there is a 25% chance for them to have sons with hypospadias. Finally, there is a 25% chance with each pregnancy that neither parent passes down the mutation, and the baby therefore does not develop hypospadias and cannot pass any mutations down to their future children.

For a male with autosomal recessive hypospadias (or an unaffected female who inherits a mutation from both parents), all of his children will be carriers of the condition.

References
  • http://ghr.nlm.nih.gov/glossary=autosomaldominant
What does autosomal dominant inheritance in hypospadias mean?

Chromosomes are the structures that hold all of our genetic information. Our genetic information is encoded as genes, which are individual instructions for our bodies to grow and develop. Chromosomes come in pairs, one that was inherited from mom and one that was inherited from dad, and therefore the genes on each chromosome also come in pairs. The first 22 pairs in humans are numbered roughly by size, and the 23rd pair, the sex chromosomes, determine sex (XX for female, XY for male). The word autosome describes any of the numbered, non-sex chromosomes. In terms of inheritance, this means that the gene associated with a genetic condition is located on one of these non-sex chromosomes.

In autosomal dominant-inherited disorders, only one copy of the gene associated with disease has a genetic change, or a mutation, that affects the function or instruction of the gene. The other copy of the gene is normal. However, having only one copy of the gene with a mutation is enough to cause symptoms. This is because the copy of the gene with the mutation "dominates" over the normal gene, resulting in the disease. In this type of inheritance, with each pregnancy, there is a 50/50 chance that the child will inherit the mutation and be affected by the disease. Typically, the gender of the baby does not matter; however, because hypospadias can only affect males, females appear symptom-free even if they inherit the mutation. This means that a female who inherited the mutation from one of her parents may have sons with hypospadias, even though she herself has no symptoms. Similarly, a male with autosomal dominant hypospadias can pass the mutation down to a son, who would also develop hypospadias, or to a daughter, who would appear symptom free, but could pass it down to her future sons. Any individual who does not inherit the mutation will not develop hypospadias and cannot pass the mutation down to their future children.

References
  • http://ghr.nlm.nih.gov/glossary=autosomaldominant
What is variable expression in hypospadias?

Hypospadias can be inherited in a variety of different ways. In each of these inheritance patterns, there is the possibility of variable expression. Variable expression means that the type and severity of the hypospadias can be different between different people, even in the same family. For example, it is possible for a father with subcoronal hypospadias to have a brother with midshaft hypospadias and a son with penoscrotal hypospadias. Variable expression makes it very difficult to predict the type and severity of hypospadias in other family members.

References
  • http://ghr.nlm.nih.gov/glossary=variableexpression
What is reduced penetrance in familial hypospadias?

The penetrance of a certain condition refers to the amount of people with a particular genetic condition that actually show signs of that condition. Reduced penetrance means that having the necessary genetic changes (mutations) is not enough to cause symptoms to show. In familial hypospadias, this means that not everyone who inherits the causative mutations will have hypospadias. This can look like a condition is "skipping generations". For example, a father with hypospadias may have a son without hypospadias, but that son's son may also have hypospadias, even though they all have the same necessary mutation for hypospadias. Reduced penetrance most likely results from a combination of genetic, environmental, and lifestyle factors.

References
  • http://ghr.nlm.nih.gov/handbook/inheritance/penetranceexpressivity
I was born with hypospadias, what are the chances that my son will also be born with hypospadias?

There is an 8% chance of a son of a man with hypospadias to also have hypospadias. This is without knowing the exact cause of the father's hypospadias (genetic and environmental factors and various types of inheritance pattern). If a particular cause (genetic or environmental) is found, this can increase or decrease the chance of having a son with hypospadias.

References
  • http://heainfo.org/index.php/category/hypospadias/
We have already had one child who had hypospadias, what are the chances that are next son will also have hypospadias?

The chance that a second son will also have hypospadias was found to be about 17% in a 1990 study that focused on familial cases of hypospadias. This means that the recurrence risk for hypospadias is 17%.

References
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1017217/
  • Stoll, C., Alembik, Y., Roth, M. P., Dott, B. Genetic and environmental factors in hypospadias. J. Med. Genet. 27: 559-563, 1990.

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