Genetic subtypes and phenotypic characteristics of 110 patients with Prader-Willi syndrome

Zhang, Lu; Liu, Xiaoliang; Zhao, Yun-Jing; Wang, Qingyi; Zhang, Yuanyuan; Gao, Haiming; Zhang, Bijun; Cui, Wanting; Zhao, Yongjun

doi:10.1186/s13052-022-01319-1

Cited by 13 publications

(17 citation statements)

References 38 publications

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“…This lack of difference in cognitive profiles may be due to higher heterogeneity inside each group. In subjects with disomy, cognitive function seems more preserved in the case of uniparental disomy, heterodisomy being more favorable than isodisomy (Zhang et al, 2022). In subjects with deletion, phenotype varies according to the length of the deletion.…”

Section: Discussionmentioning

confidence: 99%

Prader–Willi syndrome: Symptoms and topiramate response in light of genetics

et al. 2023

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IntroductionPrader–Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly.MethodsWe retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion (N = 8) or disomy (N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p-value and bootstrap 95% confidence interval computations.ResultsFirst, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion.DiscussionThese results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous disorders.

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Section: Discussionmentioning

confidence: 99%

Prader–Willi syndrome: Symptoms and topiramate response in light of genetics

et al. 2023

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“…8 Specifically, hypopigmentation, which is a symptom of suspected PWS, was observed less frequently in the UPD group than in the deletion group. 40,41 In our report, we were unable to evaluate the rates of hypopigmentation because of a lack of data on dysmorphic features. In addition, commercial unavailability of methylation testing in Japan until 2018, and use of fluorescence in situ hybridization as the first choice for detection of deletion at many facilities, may also be related to the delayed diagnosis.…”

Section: Discussionmentioning

confidence: 85%

“…The reason for later diagnosis of patients with UPD compared to those with deletions was the less typical clinical phenotype 8 . Specifically, hypopigmentation, which is a symptom of suspected PWS, was observed less frequently in the UPD group than in the deletion group 40,41 …”

Section: Discussionmentioning

confidence: 99%

Perinatal and neonatal characteristics of Prader–Willi syndrome in Japan

Oto

Murakami

Imatani

et al. 2023

Pediatrics International

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BackgroundPrader–Willi syndrome (PWS) is suspected at birth if extreme hypotonia, difficulty in feeding, hypogonadism, and failure to thrive are present. Genetic diagnosis of PWS can generally be made within the first few months of life; however, a delayed diagnosis of PWS is frequently reported. Although the clinical characteristics of perinatal and neonatal patients with PWS have been reported, there are no such reports on the clinical characteristics of these patients in Japan.MethodsThis retrospective, single‐center study involved 177 Japanese patients with PWS and their medical data regarding the perinatal and neonatal periods were evaluated.ResultsThe median maternal age at birth was 34 years; 12.7% of the mothers had a history of assisted reproductive technology (ART). Of the mothers, 13.5% reported polyhydramnios and 4.3% had oligohydramnios. Decreased fetal movement during pregnancy was reported by 76% of the mothers. A total of 60.5% of patients were born by cesarean section. Genetic subtypes included deletions (66.1%), uniparental disomy (31.0%), imprinting defects (0.6%), and other or unknown subtypes (2.3%). The median birth length was 47.5 cm and the median birthweight was 2476 g. Of the 160 patients, 14 (8.8%) were classified as small for gestational age. Most patients had hypotonia (98.8%), and 89.3% required gavage feeding at birth. Breathing problems, congenital heart disease, and undescended testis were noted in 33.1%, 7.0%, and 93.5% of patients, respectively.ConclusionIn our study, higher rates of ART, polyhydramnios, decreased fetal movements, cesarean section, hypotonia, feeding difficulties, and undescended testis were observed in PWS.

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“…51 There are two types of UPD, isoUPD and heteroUPD, which may play a part in the genotype variation, especially for anxiety. 12 However, we did not analyze difference between the subtypes of UPD and phenotypes. Further studies on the phenotypes among different subgenotypes of deletion and UPD are required.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8][9][10][11] On the other hand, UPD patients are less likely to have typical facial features, skin picking, or hypopigmentation. 1,12 However, results from different studies are not consistent. Dobrescu et al 13 found no differences between the deletion and UPD types in specific facial features, hypopigmentation, sleep disorder, obesity, and scoliosis, though they only had a total of 35 individuals with PWS in that study.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlation in Prader‐Willi syndrome: A large‐sample analysis in China

Mao,

Yang,

Gao

et al. 2024

Clinical Genetics

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The genotype–phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes of PWS in children. We aimed to explore the influence of specific gene changes on the clinical symptoms of PWS and the value of early screening and early intervention of the condition. All data in this study were extracted from the database of the XiaoPang Weili Rare Disease Care Center. The collected information included basic demographics, maternal pregnancy information, endocrine abnormalities, growth and development abnormalities, and other clinical phenotypes. The relationships between genotypes and phenotypes in the major categories of PWS were analyzed. A total of 586 PWS cases with confirmed molecular diagnosis and genotyping were included in this study. Among them, 83.8% belonged to the deletion type, 10.9% the uniparental disomy (UPD) type, and 5.3% the imprinting defect (ID) type. Age‐wide comparison among the three groups: The rate of hypopigmentation in the deletion group was higher than that in the UPD group (88.8% vs. 60.9%; p < 0.05); A total of 62 patients (14.2%) had epilepsy; and no statistical significance was found among the three groups (p = 0.110). Age‐wide comparison between the deletion and non‐deletion types: the rate of skin hypopigmentation and epilepsy in the deletion group was significantly higher than that in the non‐deletion group (88.8% vs. 68.4%, p < 0.001; 15.9% vs. 7.6%, p = 0.040). The intergroup comparison for the >2‐year age group: there were significant intergroup differences in the language development delay among the three groups (p < 0.001). The incidence of delayed language development was the highest in the deletion group, followed by the UPD group, and the lowest in the ID group. The rates of obesity and hyperphagia in the deletion group were also higher than those in the non‐deletion group (71.1% vs. 58.9%, p = 0.041; 75.7% vs. 62.0%, p = 0.016). There are significant differences in the rates of skin hypopigmentation and language developmental delay among the deletion, UPD, and ID genotypes. The patients with deletion type had significantly higher rates of lighter skin color, obesity, hyperphagia, language developmental delay, and epilepsy. The results of this study will help clinicians better understand the impact of different PWS molecular etiologies on specific phenotypes.

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Genetic subtypes and phenotypic characteristics of 110 patients with Prader-Willi syndrome

Cited by 13 publications

References 38 publications

Prader–Willi syndrome: Symptoms and topiramate response in light of genetics

Prader–Willi syndrome: Symptoms and topiramate response in light of genetics

Perinatal and neonatal characteristics of Prader–Willi syndrome in Japan

Genotype–phenotype correlation in Prader‐Willi syndrome: A large‐sample analysis in China

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