Two more rare disease genes identified

January was a good month for our exome sequencing programme, with the identification of genes associated with two more rare diseases.

Genitopatellar Syndrome (GPS)

This is an exceptionally rare, but severe, congenital disorder with abnormal development of the knee cap, genitals and nervous system. There is a characteristic facial appearance, limited/ no movement due to the absence of the knee cap, and severe mental retardation.

6 unrelated affected individuals were sequenced. The researchers found:

• Mutations in 5 of the individuals in a gene called KAT6B – 2 people had the same mutation, so 4 different mutations were identified
• All 4 mutations were in the same region of the same exon, within 66 base pairs of each other

The researchers checked the parents’ DNA and found that none of them had a mutation – all 4 mutations were new rather than inherited.

“These results shows how important our sequencing approach is,” says Dr Michael Simpson who leads the BRC's exome sequencing programme. “The traditional way to identify disease causing genes has been to use family pedigrees and/ or compare large populations of cases with controls. In this disease the mutations arise spontaneously so cannot be tracked using pedigrees, and the mutations are too rare to do large scale population comparisons. Sequencing was the only way to identify and confirm the gene involved.”

Interestingly, another disease, known as Ohdo Syndrome, was recently also associated with mutations in the KAT6B gene. The mutations are actually in the same exon, although a different region, and the disease has different symptoms. It has a characteristic facial appearance (distinct from GPS), skeletal abnormalities, and moderate mental retardation.

The KAT6B gene codes for an interesting protein, histone acetyl transferase, which modifies histones. Histones package and order DNA, which could explain why we see two different diseases associated with the same gene.

Microcephaly-Lymphoedema-Chorioretinal Dysplasia (MLCRD)

MLCRD is also a congenital disorder, where the development of the brain, eye and lymphatic system are affected.

There is a spectrum of features from one to all of:

• Microcephaly (small head)
• Lymphoedema (fluid retention and swelling) – particularly of the feet
• Chorioretinopathy – abnormality of retinal layers

In collaboration with Lymphoedema Research Group, at St George’s University of London, the team sequenced the exomes of 5 patients with MLCRD. Mutations in the KIF11 gene were identified, and further mutations were found by traditional sequencing in another 24 patients and their families.

The range and severity of symptoms varies greatly within MLCRD, even among people with the same mutation and within the same family. The researchers believe there may be other contributing genetic or environmental factors that determine how people are affected.

Further understanding of KIF11 and the protein it encodes, EG5, may shed light on the varying symptoms. EG5 is known to be important for the normal division of cells, but its role in the development of the brain, retina and lymphatic systems is not yet understood.

References

Genitopatellar Syndrome: Simpson MA, Deshpande C et al, Am J Hum Gen (Jan 2012)
MLCRD: Ostergaard P, Simpson MA et al Am J Hum Gen (Jan 2012)