Genetic conditions are caused by alterations in our genes which prevent the gene from working properly.

Our bodies are made up of many millions of cells. Nearly all cells have a structure called the nucleus, which contains chromosomes that contain genes.

Chromosomes are compact bundles of DNA. (See Box 1 below for an explanation of DNA.)

A gene is a specific section of DNA.

Body cells have two copies of each chromosome, as we inherit one copy from each parent.

We all have 46 chromosomes in each cell in our body and these are arranged in 23 pairs.

This means we have two copies of every gene.

Genes are a sequence of code (called base pairs) which are read by the body to make proteins (see Box 1 for more information). Our cells need proteins for their structure, survival and to work correctly. We each have approximately 20,000 different genes making different proteins in our bodies¹‾². Each protein made by a different gene has its own unique function. The structure of the protein, and therefore its function, is determined by the order in which the base pairs are arranged in that particular gene. Usually, there are two copies of each gene on each chromosome pair: one inherited from each parent.

Sometimes a gene can contain an alteration known as a mutation. Genetic conditions occur when a mutation within a gene affects how the protein in our bodies is produced and how it works.

People have 23 pairs of chromosomes. 22 of the pairs are non-sex chromosomes, known as autosomes, which are found in both males and females. The 23rd pair consists of two sex chromosomes which determine your sex. Females usually have two X chromosomes (XX), and males an X and a Y chromosome (XY).

Conditions described as autosomal are those in which the gene alteration (mutation) that causes the condition is located on one of the autosomes, and not on one of the two sex chromosomes. Autosomal conditions affect both males and females.

When a condition is autosomal dominant, only one parent needs to have an altered gene to pass it on.

Autosomal dominance is the inheritance pattern most often seen in:

• Distal Spinal Muscular Atrophy Type V (DSMA-V)
• Spinal Muscular Atrophy with Lower Extremity Predominance (SMA-LED)

Autosomal dominant family 1: one parent has SMA and the other does not

For each pregnancy, the chances are:

• Child will have SMA: 2 in 4 chance (50%)
• Child will not have SMA: 2 in 4 chance (50%)

Autosomal dominant family 2: both parents have SMA

If both parents have SMA and their child inherits two dominant genes, one from each parent, this can cause a very severe form of SMA and possibly other difficulties for the child as well.

For each pregnancy, the chances are:

• Child will have SMA: 3 in 4 chance (75%)
• Child will not have SMA: 1 in 4 chance (25%)

People have 23 pairs of chromosomes. 22 of the pairs are non-sex chromosomes, known as autosomes, and which are found in both males and females. The 23rd pair consists of two sex chromosomes, which determine your sex. Females usually have two X chromosomes (XX), and males usually an X and a Y chromosome (XY).

Conditions described as autosomal are those in which the gene alteration (mutation) causing the condition is located on one of the autosomal chromosomes³, and not one of the two sex chromosomes. Autosomal conditions affect both males and females.

This is the inheritance pattern most often seen in:

• Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME)
• Spinal Muscular Atrophy with Respiratory Distress (SMARD)

In an autosomal recessive pattern of inheritance, both copies of the gene must be altered for the condition to occur – one from each parent. People who have one ‘healthy’ copy and one altered copy of a gene are called carriers. They do not usually have any symptoms themselves, but the altered gene can be passed on to their children. The chances of children being carriers or having a rare form of SMA will depend on whether their parents have the condition or are carriers.

Autosomal recessive family 1: both parents are carriers

For each pregnancy, the chances are:

• Child will have SMA: 1 in 4 chance (25%)
• Child will not have SMA but will be a carrier: 2 in 4 chance (50%)
• Child will not have SMA and is not a carrier: 1 in 4 chance (25%)

Autosomal recessive family 2: one parent is a carrier, the other does not have SMA & is a non-carrier

For each pregnancy, the chances are:

• Child will have SMA: not possible (0%)
• Child will not have SMA but will be a carrier: 2 in 4 chance (50%)
• Child will not have SMA and will not be a carrier: 2 in 4 chance (50%)

Autosomal recessive family 3: one parent has SMA, the other does not have SMA and is a non-carrier

For each pregnancy, the chances are:

• Child will have SMA: not possible (0%)
• Child will not have SMA and will not be a carrier: not possible (0%)
• Child will not have SMA but will be a carrier: 4 in 4 chance (100%)

Autosomal recessive family 4: one parent has SMA, the other is a carrier

For each pregnancy, the chances are:

• Child will not have SMA and will not be a carrier: not possible (0%)
• Child will have SMA: 2 in 4 chance (50%)
• Child will not have SMA but is a carrier: 2 in 4 chance (50%)

Autosomal recessive family 5: both parents have SMA

For each pregnancy, the chances are:

• All the children will have SMA: 4 in 4 chance (100%)

In an X-linked recessive pattern of inheritance, the altered gene is on the X chromosome, but is not found on the shorter, male-specific Y chromosome. Males only have one X chromosome and therefore only one copy of the gene. This means that if they have one altered copy then they have no other healthy copy. Males are therefore much more frequently affected by X-linked disorders than females.

Females with one ‘healthy’ copy and one altered copy of the gene do not usually have any symptoms, although some have a very mild form of the condition. However, the altered gene can be passed on to their children. As a result of this they are called carriers.

This is the inheritance pattern most often seen in:

• Spinal and Bulbar Muscular Atrophy (SBMA) – also known as Kennedy’s Disease
• X-linked Infantile Spinal Muscular Atrophy

The chances of children being carriers or having a rare form of SMA will depend on whether their parents have the condition or are carriers. The chances stay the same for each pregnancy that a couple has.

X-linked recessive family 1: the mother is a carrier, the father is not a carrier and doesn’t have SMA

For each pregnancy, the chances are:

• Daughters will have a 1 in 2 chance (50%) of not having SMA and not being a carrier
• Sons will have a 1 in 2 chance (50%) of not having SMA and not being a carrier
• Daughters will have a 1 in 2 chance (50%) of being a carrier
• Sons will have a 1 in 2 chance (50%) of having SMA

X-linked recessive family 2: the mother is a carrier, the father has SMA

For each pregnancy, the chances are:

• Daughters will have a 1 in 2 chance (50%) of being a carrier
• Sons will have a 1 in 2 chance of not having SMA and not being a carrier
• Daughters will have a 1 in 2 chance (50%) of having SMA
• Sons will have a 1 in 2 chance (50%) of having SMA

X-linked recessive family 3: the mother does not have SMA and is not a carrier, the father has SMA

For each pregnancy, the chances are:

• Daughters will have a 2 in 2 chance (100%) of being a carrier
• Sons will have a 2 in 2 chance (100%) of not having SMA and not being a carrier

X-linked recessive family 4: the mother has SMA, the father does not have SMA and is not a carrier

For each pregnancy, the chances are:

• Daughters will have a 2 in 2 chance (100%) of being a carrier
• Sons will have a 2 in 2 chance (100%) of having SMA

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X-linked recessive family 5: both parents have SMA

For each pregnancy, the chances are:

• All the children will have SMA

In most cases of SMA, the gene change or changes are clearly inherited from one or both parents, who may themselves have no symptoms of SMA (particularly in autosomal recessive or X-linked recessive forms). In rarer cases, however, the genetic cause for SMA may not be present in either parent or is not clearly present in the cells analysed in the carrier test. In other words, it may be a new gene change in the affected individual. This situation can be caused by a “de novo” mutation or something known as “germline mosaicism” in a parent.

• De Novo

De novo means “from the beginning” and is a type of mutation that occurs either when an individual sperm or egg is made, when a sperm fertilises an egg, or when cells are dividing after fertilisation. The most likely reason is an error in the making of the sperm or egg cell. As it occurs at this stage, the mutation will not be detected in either of the parents.

• Germline Mosaicism

Alternatively, a parent may have something known as germline mosaicism, which is when an individual produces sperm or egg cells that differ in their genetics from all the other cell types in the body of that person. If the altered gene linked to SMA is affected in this manner, the sperm or eggs of that individual can have a faulty gene that causes SMA, which would go undetected by the carrier test.

These rare scenarios can have implications for the chance of SMA affecting a future pregnancy, and highlight the importance of having genetic counselling specific to your own circumstances.

The genetics of SMA are complex. Also, for a small number of people, their genetic circumstances are not clear. For example, for some people, a diagnosis of ‘adult onset SMA’ is made even though the genetic cause of their SMA has not been identified.

Genetic counselling is with a healthcare professional who has expert training in genetics. They will aim to explain results from your genetic testing in an easily understandable way, and answer any questions you might have about the genetic aspects of the diagnosis.

If you or your child have recently been diagnosed with a rarer form of SMA, you should be offered a referral for genetic counselling. You can also request a referral from your General Practitioner (G.P.).

More Information about Genetics and Genetic Testing:

Genetic Alliance UK

• Phone: 0207 704 3141
• Website >

Support:

SMA UK

• Phone: 01789 267520
• Email: office@smauk.org.uk
• Website >

Provides information and support for anyone in the UK affected by any form of SMA.

1. International Human Genome Sequencing Consortium (2004) ‘Finishing the euchromatic sequence of the human genome’, Nature, 431, pp. 931-945.
2. Pennisi, E. (2012) ‘ENCODE project writes eulogy for junk DNA’, Science, 337(6099), pp. 1159-1161.
3. Lefebvre, S., Bürglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frézal, J., Cohen, D., Weissenbach, J., Munnich, A., and Melki, J. (1995) ‘Identification and characterization of a spinal muscular atrophy-determining gene’, Cell, 80(1), pp. 155-165.