Kleefstra syndrome (Ks) is a rare genetic disorder characterised by intellectual disability, often accompanied by a spectrum of complex physical and clinical features. The predominant cause of Ks is a tiny piece missing (known as a deletion) from near the end of chromosome 9. However individuals with a mutation, or intragenic duplication also carry a Ks diagnosis. The deletion or mutation affects a gene called EHMT1 (Euchromatic Histone Methyltransferase 1) and it’s absence or disturbance is believed to cause the major symptoms of the syndrome. The syndrome was officially recognised as Kleefstra syndrome in April 2010. Ks has previously been known as 9q34.3 deletion syndrome, 9qSTDS (short for 9q subtelomeric deletion syndrome), 9q-Syndrome, 9q34.3 microdeletion syndrome.
There isn’t a one-size-fits-all description of Ks because there is a wide range of symptoms and an even wider range in the severity of those symptoms. The variation may be due in part to the number of damaged or deleted genes in the 9q34.3 region, but those with roughly the same deletion size can also have quite different symptoms.
Most cases of Ks are de novo meaning they are not inherited from either parent, however even though rare it has been known for a child to inherit the 9q34.3 deletion from an unaffected parent who is mosiac for the deletion. Mosiaic means that an individual has the deletion is some cells but not in others. Also very rarely individuals with Ks have been known to reproduce and pass the disorder onto their children.
Intellectual Disability or Learning Disability
Severely delayed or absent speech
Recognisable facial appearance
Low muscle tone (hypotonia) – delayed physical milestone
Structural brain abnormalities/Seizures
General loss of interest and enthusiasm (apathy) or unresponsiveness (catatonia) usually in adolescence.
Features of Autism or related developmental disorders
Minor genitourinary abnormalities
Severe respiratory infections often caused by aspiration reflux/GERD.
Less Common Features
Slightly unusual hands and/or feet (single palm crease, incurving fingers, short or tapering fingers, unusually positioned feet)
Strabismus (squint) or other unusual eye features
Connective tissue disorders, including lax joints and hernias
Anal atresia (the normal opening for the anus is not present)
High birth weight and childhood obesity
What Are Chromosomes?
Chromosomes are the structures in each of the body’s cells that carry the genetic information that tells the body how to develop and function. They come in pairs, one from each parent, and are numbered 1 to 22 approximately from largest to smallest. Each chromosome has a short (p) arm and a long (q) arm.
You can’t see chromosomes with the naked eye, but if you stain them and magnify them many hundreds of times under a microscope, you can see that each one has a distinctive pattern of light and dark bands. In the diagram of the long arm of chromosome 9 (below) you can see the bands are numbered outwards starting from the point at the top of the diagram where the short and long arms meet (the centromere). A high number such as q34 is very close to the end of the chromosome, at the bottom in the diagram. The region close to the end of the chromosome is called the subtelomere.
If you magnify chromosome 9 about 850 times, you may be able to see down a microscope that a small piece is missing. But in Kleefstra syndrome the missing piece is usually so tiny that the chromosome looks normal down a microscope. The missing section can then only be found using more sensitive molecular techniques such as FISH (fluorescence in situ hybridisation, a technique that reveals the chromosomes in fluorescent colour), MLPA (multiplex ligation-dependent probe amplification) and/or EHMT1 sequencing, a method of searching specifically for the EHMT1 gene. Commercial FISH probes can show a normal result in a child who has lost EHMT1, making correct diagnosis dependent on MLPA and/ or EHMT1 sequencing.
There are around 200 genes in the 9q34 region and EHMT1 is the second gene from the end of 9q.
The disturbance or deletion in of the EHMT1 gene alone is responsible for the features of Ks, however many individuals have other genes affected or missing from the same region which may lead to additional complications.
Some individuals have much larger deletions than others. Geneticists in the past believed that people with larger deletions were more severely affected than people with smaller deletions, because they had lost more genes. It’s now thought that individuals are likely to be affected in different ways depending on which other genes have been been affected and their importance in our genetic makeup. It’s not the number of genes deleted or disturbed that matters, rather the importance of each affected gene which can result in more severe symptoms.
Your geneticist or genetic counsellor will almost certainly give you your child’s karyotype, a way of describing what chromosomes look like. This usually shows the point(s) where the chromosome has broken.
It is likely to read something like this:
46,XY.ish del(9)(q34.3)(D9S2168-)de novo
|46||The total number of chromosomes in your child’s cells.|
|XY||The two sex chromosomes, XY for males; XX for females.|
|.ish||Analysis by FISH, a combination of conventional chromosome analysis with molecular technology.|
|del||A deletion, or material is missing.|
|(9)||The deletion is from chromosome 9.|
|(9q34.3)||The chromosome has broken at the band 9q34.3, indication a small deletion of the end of the chromosome just short of the ‘cap’ that seals it at the ‘telomere’|
|(D9S2168-)||A marker whose position on the human genome is know, in this case marker D9S2168, is missing|
|de novo||The parents’ chromosomes have been checked and no rearrangement found involving 9q34. The disorder is then very unlikely to be inherited and has occurred for the first time in this family with this child.|