Prader-Willi Syndrome: Obesity due to Genomic Imprinting

Abstract

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder due to errors in genomic imprinting with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 region. Approximately 70% of individuals with PWS have a de novo deletion of the paternally derived 15q11-q13 region in which there are two subtypes (i.e., larger Type I or smaller Type II), maternal disomy 15 (both 15s from the mother) in about 25% of cases, and the remaining subjects have either defects in the imprinting center controlling the activity of imprinted genes or due to other chromosome 15 rearrangements. PWS is characterized by a particular facial appearance, infantile hypotonia, a poor suck and feeding difficulties, hypogonadism and hypogenitalism in both sexes, short stature and small hands and feet due to growth hormone deficiency, mild learning and behavioral problems (e.g., skin picking, temper tantrums) and hyperphagia leading to early childhood obesity. Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children. The chromosome 15q11-q13 region contains approximately 100 genes and transcripts in which about 10 are imprinted and paternally expressed. This region can be divided into four groups: 1) a proximal non-imprinted region; 2) a PWS paternal-only expressed region containing protein-coding and non-coding genes; 3) an Angelman syndrome region containing maternally expressed genes and 4) a distal non-imprinted region. This review summarizes the current understanding of the genetic causes, the natural history and clinical presentation of individuals with PWS.

Keywords: Angelman syndrome; Prader-Willi syndrome; clinical presentation and differences; deletion; genetic subtypes.; genomic imprinting; maternal disomy.

Fig. (1)

(A). Frontal and profile views of a 16 month old female with Prader-Willi syndrome due to maternal disomy 15 and not treated with growth hormone. Note the typical facial features of a narrow forehead, short-upturned nose and downturned corners of the mouth. The gastrostomy site is noted along with central obesity. (B). Facial, profile and hand views of an 18 year old female with Prader-Willi syndrome due to the typical 15q11-q13 deletion and not treated with growth hormone. Note the almond-shaped eyes, a narrow forehead, thin upper lip, hypopigmentation, central obesity and small hands.

Fig. (2)

Ideogram of chromosome 15 showing the order of protein-coding and non-coding genes and transcripts in the 15q11-q13 region and location of breakpoints for the typical Type I and Type II deletions. Abbreviations: Cen, centromere; Tel, telomere; BP, breakpoint; IC, imprinting center; snoRNAs, small nucleolar RNAs.

Fig. (3)

Scatterplot of mean normalized values with standard deviations for probes evaluated by multiplex ligation-dependent probe amplification (MLPA) with methylation-specific analysis. (A) Gene copy number of a control individual without any deletion or duplication of probes in the 15q11-q13 region or elsewhere deleted (average copy number of 2.0 for each probe). (B) Gene copy number of an individual with Prader-Willi syndrome and the typical Type I deletion of the 15q11-q13 region extending from GCP5 to OCA2 with other genes on chromosome 15 (e.g., APBA2) or other chromosomes not deleted (copy number of 1.0 = deletion; copy number of 2.0 = non-deletion). (C) Gene copy number of an individual with Prader-Willi syndrome and the typical Type II deletion of the 15q11-q13 region extending from MKRN3 to OCA2 with other genes on chromosome 15 (e.g., APBA2) or other chromosomes not deleted (copy number of 1.0 = deletion; copy number of 2.0 = non-deletion).

Fig. (4)

(A) Using MLPA and methylation specific probes for imprinted genes from the 15q11-q13 region, the percent of methylation can be measured to determine a normal or abnormal (Prader-Willi syndrome) methylation pattern. If the percentage of methylation for each methylation specific probe (in bold and noted by arrows) falls between 80 to 100 percent, then the diagnosis of Prader-Willi syndrome is made but the methylation pattern will not determine the genetic status (i.e., deletion, maternal disomy or imprinting defect). (B) If the percentage of methylation for each methylation specific probe (in bold and noted by arrows) falls between 40 to 60 percent, then the diagnosis is normal (not Prader-Willi syndrome).