Specific Gene Deletions Associated with More Severe PWS Disease Symptoms
Select deletions seem to affect disease severity more than the size of deletion
An overview of patients with atypical deletions causing Prader-Willi syndrome (PWS) suggests deletions in the SNURF-SNPRN and SNORD-116 genes are crucial for developing major PWS symptoms, a new study reports.
The study “Atypical 15q11.2-q13 Deletions and the Prader-Willi Phenotype,” was published in the Journal of Clinical Medicine.
PWS is caused by the loss or defects in genes in a specific region of chromosome 15, the PWS locus. In the majority of cases, genes of the paternal chromosome 15 are deleted, or missing. These genes are related to appetite, metabolism, growth, intellectual function, and social behavior.
Genetic deletions are usually the result of random errors and might affect different numbers of genes in the PWS region (large type I or short type II). In rare cases, atypical deletions, shorter or larger than the typical ones, are identified.
Researchers in the Netherlands describe eight PWS patients (six males, two females) with atypical deletions, regarding genetic causes and their correlation with PWS symptoms.
The genetic characterization was performed by a methylation assay, which detects the methylation state of DNA. When genes are methylated, that is, when methyl groups are added to the DNA molecule, they are silenced (no activity).
All eight patients had hypotonia, meaning low muscular tone, and all the males had cryptorchidism — the absence of at least one testicle. Many presented facial characteristics typical of PWS (75%), social and emotional delays (75%), neonatal feeding problems and tube feeding (63%), intellectual disabilities (50%), history of obesity (50%), excessive food eating (50%), and sideway curvature of the spine (50%).
Previous studies identified a core PWS region — that includes SNURF and SNPRN genes — as sufficient to cause PWS typical symptoms. In this study, seven of the eight had a deletion that included the SNURF-SNPRN genes.
Severity linked to specific deletions
The patient whose deletion did not include SNURF-SNPRN genes was a 4-year-old boy who had hypotonia, developmental delay, and short stature, although within normal height. He lacked some distinctive PWS features and had an average IQ. He was not obese and didn’t have an increased appetite (hyperphagia) in the last reported evaluation at 4, an age when PWS-related weight gain typically occurs.
Another patient, an 11–year-old girl, had a deletion that included only a very small part of the SNURF- SNPRN region. She was of average height and lacked several distinctive characteristics of PWS, such as severe hypotonia and facial features. However, she had obesity and hyperphagia, and a below-average IQ. She was enrolled in special education.
According to the research team, this case, along with others reported on other studies, indicate intellectual disability in PWS might be linked to a deletion of the SNURF-SNPRN region. Those with larger deletions in the PWS region can exhibit an average IQ.
“Intellectual disability in PWS might be linked to disruption of the SNURF-SNPRN gene,” the researchers wrote.
The SNURF-SNPRN might not be the cause of low stature, however.
“None of the patients with a small deletion or point mutation in SNURF-SNPRN had short stature, which could mean that this feature of PWS might not be caused by disruption or deletion of the SNURF-SNPRN gene,” the researchers wrote.
Furthermore, in six of the eight patients, deletions were reported in the SNORD116 gene, which is known to be associated with PWS disease.
A 12-year-old girl had deletions that included both SNURF-SNPRN and SNORD116. She had severe intellectual disability and behavioral, and scoliosis. A 4-year-old boy had a relatively small deletion also comprising the SNURF-SNPRN and SNORD116 genes, and presented a below-average IQ, low functioning, and hyperphagia.
Patients with relatively larger deletions appeared not to have more severe disease, compared to those with smaller deletions, including SNURF-SNPRN and SNORD116.
In fact, the major symptoms of PWS were found in patients with deletions of SNURF-SNPRN and SNORD116 genes. Patients with deletions in either one of these genes missed some specific disease symptoms, such as short stature or intellectual disability. If both genes were deleted, the phenotype was severe, compared to patients with larger PWS deletions, however.
“Our results imply that inclusion of both SNURF-SNPRN and SNORD-116 genes in the deletion leads to a more complete PWS phenotype [disease]. A larger deletion, extending further upstream and downstream from these genes, does not cause a more severe phenotype,” the researchers wrote.
The data “suggests that both SNURF-SNRPN and SNORD116 contribute to the PWS phenotype, but that genes downstream and upstream of these genes might be less important,” they concluded.
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