THE first publication on the use of WA’s Lotterywest Next-Gen sequencing platform in a human context has been released, revealing two novel genetic aberrations that lead to the onset of a devastating neuromuscular disease in utero.
Equally significant is proof that the latest sequencing technology can be used successfully and cost-effectively in gene discovery and diagnosis of rare disease cases.
Neuromuscular disease experts, Dr Gina Ravenscroft and Professor Nigel Laing from the Western Australian Institute for Medical Research (WAIMR), and clinicians and pathologists in Western and South Australia, have identified two new variants of a gene, known to regulate glycogen availability for muscle development.
The family described in this case report showed the rare combination of two different changes in the DNA sequence for glycogen branching enzyme 1 (GBE1) leading to an accumulation of abnormal glycogen, which can no longer be used by the muscle as an energy source.
This phenomenon is more commonly known as glycogen storage disease.
The researchers discovered that this specific combination of newly identified mutations in GBE1 instead resulted in lethal multiple pterygium syndrome (MPS) in this family.
MPS is a severe form of foetal akinesia which involves the loss of motor function, resulting in impaired muscle movement.
The siblings of two consecutive pregnancies in the case study appeared paralysed by 26 weeks of gestation and lacked virtually any muscle formation.
“Up to this point in time, GBE1 mutations have not been associated with foetal akinesia,” Dr Ravenscroft says.
This adds a new phenotype to GBE1-related glycogen storage disease.
Every new genetic link to disease means progress in the clinic, as the addition of another potential indicator in genetic screening will help families at risk with better prenatal testing or preimplantation diagnosis.
“Our job is to find genetic answers for as many families as we can, but tracking the gene mutations down is a real problem,” Prof Laing says.
There are not many families in which inheritance brings recessive mutations together to cause neuromuscular disease, and if so, there is rarely fetal tissue available to study.
“With Next-Gen DNA sequencing it is now possible to get answers for single patients,” Prof Laing says.
In this study, mixing linkage analysis to locate the family-specific genetic defect with targeted Next-Gen exome sequencing of only the most likely DNA coding regions proved extremely powerful.
Yet, complimentary diagnosis based on conventional pathology and clinical biochemistry will remain essential to confirm newly identified genotype-phenotype associations underpinning rare diseases.