Prader‐Willi syndrome genetic subtypes and clinical neuropsychiatric diagnoses in residential care adults

Abstract

The historical diagnosis of Prader-Willi syndrome (PWS), a complex genetic disorder, in adults is often achieved by clinical presentation rather than by genetic testing and thus limited genetic subtype-specific psychometric investigations and treatment options. Genetic testing and clinical psychiatric evaluation using Diagnostic and Statistical Manual (DSM)-IV-TR criteria were undertaken on 72 adult residents (34 M; 38 F) from the Prader-Willi Homes of Oconomowoc (PWHO), a specialty PWS group home system. Methylation specific-multiplex ligation probe amplification and high-resolution microarrays were analyzed for methylation status, 15q11-q13 deletions and maternal uniparental disomy 15 (mUPD15). Seventy (33M; 37F) of 72 residents were genetically confirmed and 36 (51%) had Type I or Type II deletions; 29 (42%) with mUPD15 and 5 (7%) with imprinting defects from three separate families. Psychiatric comorbidities were classified as anxiety disorder (38%), excoriation (skin picking) (33%), intermittent explosive disorder ([30%-predominantly among males at 45% compared with females at 16% [OR = 4.3, 95%CI 1.4-13.1, P< 0.008]) and psychotic features (23%). Psychiatric diagnoses did not differ between mUPD15 vs deletion, but a greater number of psychiatric diagnoses were observed for the larger Type I (4.3) vs smaller Type II (3.6) deletions when age was controlled (F = 5.0, P < 0.04). Adults with PWS presented with uniformly higher rates of psychiatric comorbidities which differed by genetic subtype with gender-specific trends.

Genetic Subtype-Phenotype Analysis of Growth Hormone Treatment on Psychiatric Behavior in Prader-Willi Syndrome

“…According to this dataset, UPD is significantly associated with a higher risk for anxiety and deletions are significantly associated with a higher risk of skin picking. These findings are supported by the literature, which reports that those with UPD have greater vulnerability for developing psychoses [24], and those with deletions have higher rates of developing compulsions and self-injury [10,11,14,25].…”

“…Prader-Willi syndrome is a genetically heterogeneous disorder caused by three main molecular mechanisms by which the loss of the paternally expressed genes in the 15q11.2-q13 region occurs, generally by paternal interstitial deletions followed by maternal uniparental disomy 15 and imprinting center defects (ICD) [7][8][9][10]. Depending on the molecular mechanism causing the disorder, significant differences in the clinical presentation, primarily related to the behavioral and psychiatric phenotype, may occur [4,[10][11][12][13][14]. Those with deletions (DEL) are more likely to have severe behavioral problems, such as self-injury, food-stealing, and compulsive behaviors as well as speech articulation deficits, yet they often have a particular strength with visual-perceptual skills and jigsaw puzzles [4].…”

Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study

“…12 14 Chromosomal microarrays with SNP probes were used to detect UPD15 (heterodisomy, segmental isodisomy, total isodisomy) based on LOH15 (see figure 1C–E). Genotyping of microsatellite markers from chromosome 15 was undertaken by PCR using subject and parental DNA to identify biparental inheritance and imprinting defects in those with abnormal methylation but no recognised deletion or LOH.…”

Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders

“…While some genotype–phenotype correlations have emerged in each of the syndromes, primarily around the different molecular classes, there is a need for peripheral tissue biomarkers in humans as the phenotypes are highly variable in each disorder, and their specific subtypes do not fully explain this variability 12 . For PWS, those with the typical 15q11–q13 deletions have been reported to have lower Verbal IQ (VIQ) scores than those with matUPD 13 .…”