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.

Keywords: PWS genetic subtypes; Prader-Willi syndrome (PWS); neuropsychiatric diagnoses; residential care adults.

Figure 1

MS-MLPA results of copy number comparison with probe markers for an individual with Type I (top) and Type II (bottom) PWS deletion genetic subtypes relative to a control subject. The genomic copy number is shown on the y-axis. The circle indicates the marker probes differentiating the two deletion subtypes.

Figure 2

Figure 2a. High-resolution chromosome 15 ideogram and SNP microarray results for an individual with Type I (top) and Type II (bottom) PWS deletion genetic subtypes. The genomic copy number is shown on the y-axis. The box indicates the deleted 15q11-q13 region and break points (BP1, BP2 and BP3) and the circle indicates the marker probes differentiating the two deletion subtypes. Figure 2b. High-resolution chromosome microarrays using CNV and SNP probes to identify maternal uniparental disomy 15 subclasses (segmental isodisomy, isodisomy and heterodisomy) in those with an abnormal DNA methylation pattern for PWS. Heterodisomy 15 can resemble normal biparental inheritance.

Figure 2

Figure 2a. High-resolution chromosome 15 ideogram and SNP microarray results for an individual with Type I (top) and Type II (bottom) PWS deletion genetic subtypes. The genomic copy number is shown on the y-axis. The box indicates the deleted 15q11-q13 region and break points (BP1, BP2 and BP3) and the circle indicates the marker probes differentiating the two deletion subtypes. Figure 2b. High-resolution chromosome microarrays using CNV and SNP probes to identify maternal uniparental disomy 15 subclasses (segmental isodisomy, isodisomy and heterodisomy) in those with an abnormal DNA methylation pattern for PWS. Heterodisomy 15 can resemble normal biparental inheritance.

Figure 3

Distribution of chromosome 15 bands involved in segmental isodisomy 15 by high-resolution chromosome microarrays found in 15 adults with PWS residing at the PWHO group home.

Figure 4

Figure 4a. Analysis of covariance model of the number of psychiatric disorders by age in years with a significant impact of age for Type I vs Type II deletion PWS genetic subtypes with more psychiatric disorders seen in the Type I deletion subgroup. Figure 4b. Analysis of covariance model of body mass index (BMI) by age in years for Type I vs Type II deletion PWS genetic subtypes.

Figure 4

Figure 4a. Analysis of covariance model of the number of psychiatric disorders by age in years with a significant impact of age for Type I vs Type II deletion PWS genetic subtypes with more psychiatric disorders seen in the Type I deletion subgroup. Figure 4b. Analysis of covariance model of body mass index (BMI) by age in years for Type I vs Type II deletion PWS genetic subtypes.