Different Genetic Causes Found to Determine Frequency of PWS Symptoms

Study: Cognitive, behavioral symptoms depend on genetic subtype

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Prader Willi syndrome symptoms | Prader-Willi News | illustration of DNA

The frequency of certain cognitive and behavioral symptoms in children with Prader-Willi syndrome (PWS) depends on their specific type of genetic defects, according to a study in China looking at more than 100 patients.

Notably, a deletion of paternal genes on chromosome 15 — the most common cause of Prader-Willi — was associated with more skin picking and lighter skin patches, but less frequent anxiety and autistic traits than the second-most common PWS cause, known as maternal uniparental disomy, or UPD.

These findings expand knowledge on the links between genetics and clinical features in PWS patients, which may help increase awareness of the disease and promote its early recognition and diagnosis, the researchers noted.

The study, “Genetic subtypes and phenotypic characteristics of 110 patients with Prader-Willi syndrome,” was published in the Italian Journal of Pediatrics.

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PWS is caused by the loss of or defects in genes located on the paternally inherited chromosome 15. These genes control appetite, metabolism, growth, intellectual function, and social behavior.

The most common cause of the disease, occurring in 65–75% of cases, is a deletion in this region. That’s followed by maternal UPD, or the inheritance of two copies of chromosome 15 from the mother rather than one from each biological parent. UPD occurs in 20–30% of cases.

Deletions are mainly classified as type I or II based on the most common deleted regions in chromosome 15. Maternal UPD can be divided into isodisomy and heterodisomy. Isodisomy refers to the inheritance of two exact copies of a chromosome from the mother, while heterodisomy describes the inheritance of both chromosomes in a maternal pair.

The genetic disease is characterized by low muscle tone and feeding difficulties in the first months of life, followed by excessive appetite, developmental delay and/or intellectual disability, and behavioral problems, such as anxiety, skin picking, and autistic traits. Different facial features and hypopigmentation, or patches of lighter skin tone, also are common.

Increasing research suggests that PWS genetics influence clinical features, but with inconsistent results. In addition, clinical differences between UPD subtypes and deletion subtypes remain largely unknown.

Genetic causes and symptoms in Prader-Willi syndrome

With this in mind, a team of researchers in China analyzed the genetic and clinical data of 110 children with PWS.

In all, 8,572 children with developmental delay and/or intellectual disability and/or suspected PWS features underwent genetic testing from July 2013 to December 2021 at a single Chinese hospital. Just under 1.3% were diagnosed with Prader-Willi.

Most (82.7%) of the PWS children had chromosome 15 deletions — classified as type I in 29 children, type II in 56 children, and atypical in six. The remaining 19 children (17.3%) showed heterodisomy UPD (11 children) or isodisomy UPD (eight children).

Based on available clinical data from 104 of the children, the researchers found that those in the UPD group had significantly more anxiety (64.29% vs. 26.09%) and autistic traits (57.14% vs. 26.09%) than the deletion group.

In contrast, PWS due to UPD was associated with a lower frequency of hypopigmentation (42.11% vs. 68.24%) and skin picking (42.86% vs. 71.01%) relative to that caused by chromosome 15 deletions.

Notably, children with UPD were born to significantly older mothers than those in the deletion group. The mothers’ ages at childbirth were 31.4 years for the UPD children versus 27.8 years for those with deletions.

Within the deletion group, children with type I deletion were diagnosed at a significantly earlier age (3.7 vs. 6.2 years) and were more frequently affected by speech delay (95.45% vs. 63.83%) than those with type II deletion.

The six children with atypical deletions showed a variable clinical profile. A child with a smaller deletion than type II had mild symptoms, while two children carrying smaller deletions than type I showed “unremarkable differences to the majority of PWS patients,” the researchers wrote.

More severe genetic alterations, detected in three children, were linked to more severe symptoms.

In addition, within the UPD group, the isodisomy subtype was associated with a significantly higher frequency of anxiety than the heterodisomy subtype (83.33% vs. 50%).

A total of 21 children (19.09%) received standard growth hormone therapy for more than one year, which was started at a median age of 2.1 years.

Treatment significantly improved the children’s height, but not their weight or body mass index (a ratio of weight to height). No significant changes were found in thyroid function, which is typically deficient in PWS patients, or sugar/fat metabolism.

“This study provided detailed genetic and [clinical features] of 110 PWS patients diagnosed from 8,572 Chinese pediatric individuals,” the researchers wrote, noting that the data shed light on the links between PWS genetics and clinical features.

These findings may help “promote awareness of this complex neurodevelopmental disorder,” and improve “pediatricians’ recognition and early diagnosis of PWS,” the team concluded.