DiagnosisClinical DiagnosisConsensus diagnostic criteria for Prader-Willi syndrome (PWS) developed in 1993 [Holm et al 1993] have proven to be accurate [Gunay-Aygun et al 2001] and continue to be useful for the clinician. However, confirmation of the diagnosis requires molecular genetic testing, which was not widely available when the criteria were developed. Findings that should prompt diagnostic testing have been proposed based on analysis of satisfied diagnostic criteria in individuals in whom the diagnosis of PWS has been molecularly confirmed [Gunay-Aygun et al 2001]. These differ by age group. The presence of all of the following findings at the age indicated is sufficient to justify DNA methylation analysis for PWS (see Molecular Genetic Testing):Birth to age two years. Hypotonia with poor suck (neonatal period)Age two to six yearsHypotonia with history of poor suckGlobal developmental delayAge six to 12 yearsHistory of hypotonia with poor suck (hypotonia often persists)Global developmental delayExcessive eating with central obesity if uncontrolledAge 13 years to adulthoodCognitive impairment, usually mild intellectual disabilityExcessive eating with central obesity if uncontrolledHypothalamic hypogonadism and/or typical behavior problemsTestingCytogenetic/FISH analysis. Approximately 70% of individuals with PWS have a deletion on one number 15 chromosome involving bands 15q11.2-q13, which can be detected using high-resolution chromosome studies and fluorescence in situ hybridization (FISH) testing.Note: The typical deletion is one of two sizes: extending from the distal breakpoint (BP3) to one of two proximal breakpoints (BP1 or BP2). Clinical FISH testing detects both of these deletions and typically will not distinguish between them. In addition, there are other atypical and unique deletions that occur in approximately 8% of deletion cases [Kim et al 2012].Approximately 1% of affected individuals have a detectable chromosomal rearrangement resulting in a deletion of bands 15q11.2-q13.Fewer than 1% of individuals have a balanced chromosomal rearrangement breaking within 15q11.2-q13 and detectable by chromosome analysis and FISH.Molecular Genetic TestingGene. More than 99% of individuals with PWS have a diagnostic abnormality in the parent-specific DNA methylation imprint within the Prader-Willi critical region (PWCR).Clinical testingDNA methylation analysis. DNA methylation analysis is the only technique that will diagnose PWS in all three molecular classes (paternal deletion, maternal uniparental disomy [UPD] 15 and imprinting defect [ID]) as well as differentiate PWS from Angelman syndrome (AS) in deletion cases [Glenn et al 1996, Kubota et al 1996, Glenn et al 1997]. A DNA methylation analysis consistent with PWS is sufficient for clinical diagnosis (though not for genetic counseling purposes). It does not require parental DNA samples to differentiate the maternal and paternal alleles. The most robust (and now most widely used) assay targets the 5’ CpG island of the SNURF-SNRPN (typically referred to as SNRPN) locus, and it will correctly diagnose PWS in more than 99% of cases [Glenn et al 1996, Kubota et al 1997]. The promoter, exon 1 and intron 1 region of SNRPN are unmethylated on the paternally expressed allele and methylated on the maternally repressed allele. Normal individuals have both a methylated and an unmethylated SNRPN allele, while individuals with PWS have only the maternally methylated allele. Methylation-specific multiplex-ligation probe amplification (MS-MLPA) can also determine the parental origin in this region [Kim et al 2012].
While DNA methylation should be a first line test for diagnosis, it cannot distinguish the molecular class (i.e., deletion, UPD, or ID). Therefore, once the diagnosis of PWS is established by DNA methylation analysis, determination of the molecular class is the next step. This determination is important for genetic counseling as well as genotype-phenotype correlation.Deletion analysis by fluorescence in situ hybridization (FISH) or chromosomal microarray (CMA). Deletions of 15q11.2-q13 have traditionally been diagnosed with chromosomal analysis using fluorescence in situ hybridization (FISH) with the SNRPN probe [Glenn et al 1997]. With the increasing use of chromosomal microarrays (CMA) in clinical genetics, arrays may replace FISH analysis for the identification of deletions in PWS (and AS). However, each technique has advantages. CMA will precisely identify the deletion size, which is anticipated to become increasingly important for genotype-phenotype correlations in the future [Kim et al 2012]. However, CMA will not identify the rare chromosomal rearrangements (translocations and inversions) involving proximal 15 which are detectable by simultaneous karyotype and FISH analysis and are important in recurrence risk determination. For genetic counseling purposes, a chromosomal analysis is advised in the proband to discern an interstitial de novo deletion from a balanced or unbalanced chromosomal rearrangement involving the 15q11.2 region. A CMA would also be indicated if an individual with PWS had a more severe phenotype than is typical in order to discern if there was a larger deletion present or an additional chromosomal abnormality elsewhere in the genome.Uniparental disomy analysis. UPD is detected using DNA polymorphism analysis, typically using single nucleotide polymorphism (SNP) or microsatellite analysis, which requires a DNA sample from both parents and the proband. SNP-based CMA will identify some cases of maternal UPD, but DNA polymorphism analysis is the gold standard.Imprinting defect (ID) analysis. An ID is presumed to be present in individuals who have a maternal-only DNA methylation analysis, but who have biparental inheritiance of chromosome 15. IDs caused by microdeletions in the imprinting center (IC) are detected using DNA sequence analysis or MLPA of the PWS-SRO (smallest region of overlap). Most IDs are epimutations (i.e., alterations in the imprint, not the DNA sequence) and cannot be detected by sequence analysis [Buiting et al 1998, Buiting et al 2003, Horsthemke & Buiting 2006]. Table 1. Summary of Testing Used in Prader-Willi SyndromeView in own windowTest MethodMolecular Classes DetectedProportion of PWS Detected by Test MethodTest AvailabilityDNA methylation ^{1Deletions, UPD & ID>99%Clinical MS-MLPA2Deletions, UPD & ID>99%FISH 3Deletions65%-75%DNA polymorphisms 4UPD and ID20%-30%CMA 5Deletions65%-75%DNA sequence 6ID with IC deletions<1%UPD = uniparental disomyID = imprinting defectIC = imprinting center1. Will not distinguish molecular class; can be done by Southern blot or methylation-specific PCR.2. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA): • Will distinguish deletion from disomy (UPD and ID).  • Detects five parent-specific methylation sites.  • Will not distinguish UPD from ID.  • Can give approximate size of deletion and identify type 1 and 2 deletions (see Figure 2).  • Can also detect most IC and SNORD116 microdeletions (see Figure 2; Molecular Genetic Pathogenesis).3. FISH is typically done in conjunction with a karyotype. Information is limited to AS/PWS region and the specific probes used (e.g., SNRPN). Does not query the whole AS/PWS region and it will miss small deletions. Does not give information about the rest of the chromosomes, and does not distinguish normal, UPD, and ID.4. Not a first line test. Performed after DNA methylation analysis diagnoses PWS, but FISH or CMA analysis indicates disomy.5. Chromosomal microarray (CMA) has a slightly higher detection frequency than FISH and will provide detailed information regarding size of the deletion. Also, it gives information regarding deletions and duplication in the remainder of the genome. Much more precise than karyotype and FISH. CMA will detect SNORD116 microdeletions (see Figure 2 and Molecular Genetic Pathogenesis) and some cases of UPD.6. DNA sequencing has very specific role in IDs to distinguish IC deletions from epimutations. It is limited to a region of <4.3 kb in the PWS IC smallest region of deletion overlap (SRO) [Ohta et al 1999]. The map location is approximately 25,196,494 to 25,200,794 bp [UCSC Genome Browser, hg19]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. DNA methylation analysis will diagnose PWS in all three molecular classes as well as differentiate PWS from AS in deletion cases identified by CMA and FISH 15q11.2 analysis.DNA methylation analysis consistent with PWS is sufficient for clinical diagnosis (though not for genetic counseling purposes). See Figure 1 for a comprehensive testing strategy.FigureFigure 1. Algorithm for genetic testing for Prader-Willi syndrome (PWS)
FISH = fluorescence in situ hybridization
CMA = chromosomal microarray
UPD = uniparental disomy
IC = imprinting center
MLPA = multiplex (more...)For recurrence risk assessment. If the DNA methylation pattern is characteristic of maternal inheritance only, the underlying molecular class (deletion, UPD, or ID) should be determined for genetic counseling purposes (Figure 1).It is typically most efficient to begin with FISH for the 15q11.2-q13 deletion. Simultaneous cytogenetic studies allow detection of a translocation or other anomaly involving proximal 15q. With the increasing use of chromosomal microarray (CMA) in clinical genetics, arrays may replace FISH analysis for the identification of deletions in PWS (and AS). However, each technique has its advantages. CMA will precisely identify the deletion size, which is anticipated to become increasingly important for genotype-phenotype correlations in the future [Kim et al 2012]. However, CMA will not detect the rare chromosomal rearrangements (translocations and inversions) involving proximal 15q which are detectable by simultaneous karyotype and FISH analysis and are important in recurrence risk determination. For genetic counseling purposes, a chromosomal analysis is advised in the proband to discern an interstitial de novo deletion from a balanced or unbalanced chromosomal rearrangement involving the 15q11.2 region. A CMA would also be indicated if an individual with PWS had a more severe phenotype than is typical in order to discern if there was a larger deletion present or an additional chromosomal abnormality elsewhere in the genome.If no deletion or other chromosomal abnormality is detected, DNA polymorphism studies (requiring blood from both parents and the proband) are conducted.If UPD is not detected, referral to a specialized laboratory for microdeletion analysis of the imprinting center (IC) should be done. For prenatal diagnosis and preimplantation genetic diagnosis (PGD). Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing abnormality (deletion, UPD, or ID) in the family.Genetically Related (Allelic) DisordersAngelman syndrome (AS) is caused by loss of the maternally contributed PWS/AS region. It is clinically distinct from PWS.Maternally inherited duplication of the PWS/AS region causes intellectual disability, seizures, and autism.}

Natural HistoryFetal size is generally normal. Prenatal hypotonia usually results in decreased fetal movement, abnormal fetal position at delivery, and increased incidence of assisted delivery or cesarean section.Infantile hypotonia is a nearly universal finding, causing decreased movement and lethargy with decreased spontaneous arousal, weak cry, and poor reflexes, including poor suck. The hypotonia is central in origin, and neuromuscular studies including muscle biopsy, when done for diagnostic purposes, are generally normal or show nonspecific signs of disuse.The poor suck and lethargy result in failure to thrive in early infancy, and enteral tube feeding or the use of special nipples is generally required for a variable period of time, usually weeks to months. By the time that the child is drinking from a cup or eating solids, a period of approximately normal eating behavior occurs.The hypotonia improves over time. Adults remain mildly hypotonic with decreased muscle bulk and tone.Delayed motor development is present in 90%-100% of children with PWS, with average early milestones achieved at about double the normal age (e.g., sitting at 12 months, walking at 24 months). Language milestones are also typically delayed. Intellectual disabilities are generally evident by the time the child reaches school age. Testing indicates that most persons with PWS fall in the mildly intellectually disabled range (mean IQ: 60s to 70s), with approximately 40% having borderline disability or low-normal intelligence and approximately 20% having moderate disability. Regardless of measured IQ, most children with PWS have multiple severe learning disabilities and poor academic performance for their intellectual abilities [Whittington et al 2004a]. Although a small proportion of affected individuals have extremely impaired language development, verbal ability is a relative strength for most.In both sexes, hypogonadism is present and manifests as genital hypoplasia, incomplete pubertal development, and infertility in the vast majority. Genital hypoplasia is evident at birth and throughout life.In males, the penis may be small, and most characteristic is a hypoplastic scrotum that is small, poorly rugated, and poorly pigmented. Unilateral or bilateral cryptorchidism is present in 80%-90% of males.In females, the genital hypoplasia is often overlooked; however, the labia majora and minora and the clitoris are generally small from birth.The hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Precocious adrenarche occurs in approximately 15%-20%. Infertility is the rule, although a few instances of reproduction in females have been reported [Akefeldt et al 1999; Schulze et al 2001; Vats & Cassidy, unpublished data]. Although the hypogonadism in PWS has long been believed to be entirely hypothalamic in origin, recent studies have suggested a combination of hypothalamic and primary gonadal deficiencies [Eldar-Geva et al 2009, Hirsch et al 2009, Eldar-Geva et al 2010], a conclusion largely based on the absence of hypogonadotropism and abnormally low inhibin B levels in some affected individuals of both sexes. In one study of 84 individuals with PWS (half males, half females) ages 2-35 years [Crino et al 2003], the following were identified:In males. Cryptorchidism 100%, small testes 76%, scrotal hypoplasia 69%In females. Labia minora and/or clitoral hypoplasia 76%, primary amenorrhea 56%, spontaneous menarche (mostly spotting) 44% of those over age 15 yearsIn both sexes. Premature pubarche 14%, precocious puberty 3.6% (1 male, 2 females) In contrast to the long-held view that there are only two distinct nutritional phases in PWS (i.e., failure to thrive followed by hyperphagia leading to obesity) a recent collaborative study [Miller et al 2011] found that the transition between nutritional phases is much more complex, with seven different nutritional phases through which individuals with PWS typically progress (Table 2). Table 2. Nutritional Phases in PWSView in own windowPhaseMedian AgesClinical Characteristics0Prenatal - birthDecreased fetal movements & lower birth weight than sibs1a0-9 monthsHypotonia with difficulty feeding & decreased appetite1b9-25 monthsImproved feeding & appetite; growing appropriately2a2.1-4.5 yearsWeight increasing without appetite increase or excess calories2b4.5-8 yearsIncreased appetite & calories, but can feel full38 years - adulthoodHyperphagic, rarely feels full4AdulthoodAppetite is no longer insatiable for someMiller et al [2011]The hyperphagia that occurs in PWS is believed to be caused by a hypothalamic abnormality resulting in lack of satiety. Food-seeking behavior, with hoarding or foraging for food, eating of inedibles, and stealing of food or money to buy food, are common. In most, gastric emptying is delayed, and vomiting is rare. Obesity results from these behaviors and from decreased total caloric requirement. The latter is due to decreased resting energy expenditure resulting from decreased activity and decreased lean body mass (primarily muscle) compared with unaffected individuals. The obesity in PWS is primarily central (abdomen, buttocks and thighs) in both sexes, and interestingly, there is less visceral fat in obese individuals than would be expected for the degree of obesity. Obesity and its complications are the major causes of morbidity and mortality (see Morbidity and mortality).Several independent groups have shown that ghrelin levels are significantly elevated in hyperphagic older children and adults with PWS before and after meals [Cummings et al 2002, Delparigi et al 2002, Haqq et al 2003b]. Ghrelin is a potent circulating orexigenic hormone that is produced mainly in the stomach. Circulating ghrelin levels rise after fasting and are suppressed by food intake. The appetite-inducing effect acts through the appetite regulating pathway in the hypothalamus. Ghrelin levels are lower in non-PWS obese individuals than in lean controls, and they decrease with age [Scerif et al 2011]. A small study of nine non-hyperphagic children with PWS (age 17-60 months) found similar levels of circulating ghrelin as in the eight control children matched for BMI, age, and sex [Erdie-Lalena et al 2006]. By contrast, in a larger and younger study cohort of 40 children and adolescents with PWS (range: 0.2-17.2 years; median age: 3.6 years), ghrelin levels were significantly elevated in the PWS group at any age compared to 84 age- and BMI-matched controls [Feigerlová et al 2008]. In fact, the highest ghrelin levels in PWS were found in the youngest children. Thus, in their study the hyperghrelinemia occurred at an age long before the development of obesity and increased appetite in PWS. Furthermore, several groups have now shown that pharmacologic reduction of ghrelin to normal levels in PWS, using either short- or long-acting agents, did not affect the weight, appetite, or eating behavior in hyperphagic individuals [Haqq et al 2003a, Tan et al 2004, DeWaele et al 2008]. At this time there are no consistently identified hormonal abnormalities to explain the hyperphagia, and the metabolic correlates of hyperphagia in PWS are still uncertain.Up to 25% of adults with PWS (particularly those with significant obesity) have type 2 diabetes [Butler et al 2002] with a mean age of onset of 20 years. Central hypothyroidism, with a normal thyroid-stimulating hormone value and low free thyroxine level, has been documented in up to 25% of individuals with PWS, with a mean age of diagnosis and treatment of two years [Miller et al 2008, Diene et al 2010]. Central adrenal insufficiency (CAI) following overnight single-dose metyrapone tests was noted in 60% of children with PWS in one study, suggesting that this may be the cause of the high incidence of sudden death in this population [de Lind van Wijngaarden et al 2008]. It is known that introducing GH therapy can precipitate adrenal crisis in individuals with incipient adrenal insufficiency by accelerating the peripheral metabolism of cortisol, which may explain the correlation between the incidence of sudden death at the beginning of GH treatment and CAI in individuals with PWS [Scaroni et al 2008]. However, subsequent studies have found normal cortisol responses to low- and high-dose synacthen testing, as well as to insulin tolerance testing [Nyunt et al 2010, Farholt et al 2011], so whether CAI is a true issue for individuals with PWS remains uncertain at this time and there is no consensus among endocrinologists as to whether evaluation for CAI should be performed on every individual with PWS or only those with symptoms consistent with adrenal insufficiency.Sleep abnormalities are well documented and include reduced REM (rapid eye movement) latency, altered sleep architecture, oxygen desaturation, and both central and obstructive apnea [Festen et al 2006, Priano et al 2006]. Primary hypothalamic dysfunction is thought to be the cause of the alterations in sleep microstructure and abnormalities in ventilation during sleep, with studies showing low levels of orexin and hypocretin in the cerebrospinal fluid and decreased levels of acetyl-cholinergic neurons in the pedunculo-pontine tegmental nucleus [Dauvilliers et al 2003, Nevsimalova et al 2005, Bruni et al 2010, Hayashi et al 2011]. Some individuals with PWS have excessive daytime sleepiness, which resembles narcolepsy, with rapid onset of REM sleep and decrease in non-REM sleep instability [Bruni et al 2010].A characteristic behavior profile with temper tantrums, stubbornness, controlling and manipulative behavior, compulsivity, and difficulty with change in routine becomes evident in early childhood in 70%-90% of individuals with PWS.Many of the behavioral characteristics are suggestive of autism; one study showed that 19% of 59 individuals with PWS versus 15% of age-, sex-, and IQ-matched controls satisfy diagnostic criteria for autism [Descheemaeker et al 2006].In another study of 58 children, attention deficit/hyperactivity symptoms and insistence on sameness were common and of early onset [Wigren & Hansen 2005].This behavior disorder has been reported to increase with age and body mass index (BMI) [Steinhausen et al 2004], although it diminishes considerably in older adults [Dykens 2004].Psychosis is evident by young adulthood in 10%-20% of affected individuals [Boer et al 2002, Clarke et al 2002, Vogels et al 2004].Behavioral and psychiatric problems interfere most with the quality of life in adolescence and adulthood.Short stature, if not apparent in childhood, is almost always present during the second decade in the absence of growth hormone (GH) replacement, and lack of a pubertal growth spurt results in an average untreated height of 155 cm for males and 148 cm for females. The hands and feet grow slowly and are generally below the fifth centile by age ten years, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm.Data from at least 15 studies involving more than 300 affected children [Burman et al 2001] document reduced GH secretion in PWS. GH deficiency is also seen in adults with PWS [Grugni et al 2006, Hoybye 2007]Characteristic facial features (narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, thin upper lip with down-turned mouth) may or may not be apparent at birth and slowly evolve over time.Hypopigmentation of hair, eyes, and skin resulting from a tyrosinase-positive albinoidism occurs in about one third of affected individuals.Strabismus is seen in 60%-70%.Hip dysplasia occurs in approximately 10%-20% [West & Ballock 2004, Shim et al 2010].Scoliosis, present in 40%-80%, varies in age of onset and severity.Up to 50% of affected individuals may have recurrent respiratory infections.Rates of the following are increased: Bone fractures caused by osteopeniaLeg edema and ulceration (especially in the obese) Skin pickingAltered temperature sensation Decreased saliva flowHigh vomiting thresholdSeizures (in 10%-20%)Morbidity and mortality. Mortality rate in PWS is higher than in controls with intellectual disability, with obesity and its complications being factors [Einfeld et al 2006]. Based on a population study, the death rate has been estimated at 3% per year [Butler et al 2002]. Two multicenter series of individuals who died of PWS have been reported [Schrander-Stumpel et al 2004, Stevenson et al 2004], and an extensive case and literature review of 64 cases of death in PWS was performed [Tauber et al 2008]. Respiratory and other febrile illnesses were the most frequent causes of death in children, and obesity-related cardiovascular problems and gastric causes or sleep apnea were most frequent in adults. Other causes of morbidity include diabetes mellitus, thrombophlebitis, and skin problems (e.g., chronic edema, infection from skin picking).A few individuals have been reported to have respiratory or gastrointestinal infections resulting in unexpected death; of these, three who died as a result were noted to have small adrenal glands [Stevenson et al 2004], although this is not a common finding. The recent report of central adrenal insufficiency in 60% of tested individuals [de Lind van Wijngaarden et al 2008] suggests a possible explanation for some of these unexpected and sudden deaths.Acute gastric distention and necrosis have been reported in a number of individuals with PWS [Stevenson et al 2007a], particularly following an eating binge among those who are thin but were previously obese. It may be unrecognized because of high pain threshold and can be fatal.Choking, especially on hot dogs, has been reported as cause of death in approximately 8% of deaths in individuals with PWS [Stevenson et al 2007b].Concern about the possible contribution of growth hormone (GH) administration to unexpected death has been raised by reported deaths of individuals within a few months of starting GH therapy [Eiholzer 2005, Sacco & Di Giorgio 2005]. The few reported deaths were mostly in obese individuals who had pre-existing respiratory or cardiac disorders with evidence of upper airway obstruction and uncorrected tonsillar and adenoidal hypertrophy. In the database of one pharmaceutical company, five of 675 children treated with GH died suddenly of respiratory problems [Craig et al 2006]. In another study, the rate of death in affected individuals on and off GH did not differ [Nagai et al 2005]. A study of the natural history of PWS in one region of the UK found the overall death rate of individuals with PWS to be as high as 3% per year without GH therapy [Whittington et al 2001]. Thus, the relationship of GH administration to unexpected death remains unclear. However, a recent long-term study of 48 treated children suggests that the benefits of treatment exceed the risks [Carrel et al 2010]. Neuroimaging. In a recent study, all 20 individuals with PWS who were evaluated had brain abnormalities that were not found in 21 sibs or 16 individuals with early-onset morbid obesity who did not have PWS [Miller et al 2007]. All had ventriculomegaly; 50% had decreased volume of brain tissue in the parietal-occipital lobe; 60% had Sylvan fissure polymicrogyria; and 65% had incomplete insular closure. In another study, these authors reported white matter lesions in some people with PWS [Miller et al 2006]. A study of brain MRIs from 91 individuals with PWS from another group showed reduced pituitary height in 49% and some neuroradiologic abnormality in 67% [Iughetti et al 2007]. The implications of these findings are unknown.

Genotype-Phenotype CorrelationsNo phenotypic feature is known to correlate exclusively with any one of the molecular classes of mutation that result in PWS. However, there are some statistical differences in the frequency or severity of some features between the two largest molecular classes (deletion and UPD). UPDPost-term delivery is more common with UPD [Butler et al 2009]. Individuals with UPD are less likely to have the typical facial appearance, hypopigmentation, or skill with jigsaw puzzles [Dykens 2002]; they also have a somewhat higher verbal IQ and milder behavior problems [Dykens et al 1999, Roof et al 2000, Hartley et al 2005].Individuals with UPD are more likely to have psychosis [Holland et al 2003] and autism spectrum disorders [Veltman et al 2004, Whittington et al 2004b, Veltman et al 2005, Descheemaeker et al 2006]. Recent studies suggest that as many as 62% of those with UPD develop atypical psychosis compared with 16% of those with a deletion [Soni et al 2007].DeletionIndividuals with a deletion showed a higher frequency of need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects in a recent study of 91 children [Torrado et al 2007].Individuals with the slightly larger, type 1 deletions (BP1 to BP3; see Figure 2) have been reported to have more compulsions and poorer adaptive behavior, intellectual ability, and academic achievement than those with type 2 deletions (BP2 to BP3) [Butler et al 2004, Hartley et al 2005]. Two other studies found much less clinically significant differences between individuals with these two deletion types [Milner et al 2005, Varela et al 2005].FigureFigure 2. Summary of the genetic and expression map of chromosomal region 15q11.2-q13
The Prader-Willi syndrome (PWS) region (shown in blue) has 5 paternal-only (PWS region) expressed unique copy genes that encode polypeptides (MKRN3, (more...)

Differential DiagnosisMany disorders can mimic parts of the PWS phenotype.Craniopharyngioma and the results of its treatment show the greatest overlap with PWS. Damage to the hypothalamus causes most of the same findings that characterize PWS, particularly when craniopharygioma occurs at an early age. History and, if uncertain, methylation analysis will distinguish craniopharyngioma from PWS.Hyperphagic short stature is an acquired condition related to psychosocial stress that includes growth hormone insufficiency, hyperphagia, and mild learning disabilities [Gilmour et al 2001]. History and, if uncertain, methylation analysis should distinguish this disorder from PWS.Hypotonia in infancy is also seen in the following conditions:Neonatal sepsisCentral nervous system depressionCongenital myotonic dystrophy type 1, characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common. It is caused by expansion of a CTG trinucleotide repeat in DMPK.Several myopathies and neuropathies, including some instances of spinal muscular atrophy (SMA) [Miller et al 1999, Richer et al 2001]. In these situations, poor respiratory effort may be present, a feature rarely seen in PWS. Molecular genetic testing, EMG/NCV, and/or muscle biopsy are often required to differentiate these conditions.Angelman syndrome (AS), characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. AS is caused by absence of expression of the maternal copy of UBE3A and may be diagnosed in 75%-80% of individuals with AS using DNA methylation analysis of chromosome 15. In infancy, hypotonia may be the only manifestation of AS. Affected individuals lack the characteristic sucking problems, hypogonadism, and facial appearance of PWS.Fragile X syndrome, characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Males may have a characteristic appearance (large head, long face, prominent forehead and chin, protuding ears), connective tissue findings (joint laxity), and large testes (postpubertally). Behavioral abnormalities, sometimes including autism spectrum disorder, are common (see Autism Overview). The diagnosis of fragile X syndrome rests on the detection of an alteration in FMR1 consisting of expansion of a triplet repeat and gene methylation. In infancy, hypotonia may be the only manifestation of AS. Affected individuals lack the characteristic sucking problems, hypogonadism, and facial appearance of PWS.In childhood, MECP2-related disorders (see MECP2-Related Disorders) can present with hypotonia, obesity, and gynecomastia as well as intellectual disability. Beginning at ages six to 18 months, affected girls enter a short period of lack of progress followed by rapid regression in language and motor skills. The hallmark of the disease is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements. Affected individuals lack the characteristic sucking problems, hypogonadism, and facial appearance of PWS. Genetic testing of MECP2 can establish the diagnosis of Rett syndrome in most affected girls.Developmental delay/intellectual disability and obesity with or without hypogonadism can be seen in the following disorders:Angelman syndrome (AS) Fragile X syndromeMaternal uniparental disomy for chromosome 14, which also includes prenatal growth retardation, feeding problems, short stature, and precocious puberty [Cox et al 2004, Hosoki et al 2009] Albright hereditary osteodystrophy, which also includes short stature, but lacks hypotonia and has different characteristic facial appearance (round face). Specific testing is possible by measurement of Gs receptor-coupling protein.Bardet-Beidl syndrome (BBS), characterized by cone-rod dystrophy, dystruncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction. It has a different facial phenotype from PWS. Inheritance is typically autosomal recessive, although in fewer than 10% of individuals inheritance may be more complex.Cohen syndrome, characterized by downslanting palpebral fissures, short philtrum, large central incisors, tapered fingers, and more severe intellectual disability. Microcephaly, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia are also present. Cohen syndrome is caused by mutations in COH1. Inheritance is autosomal recessive.Borjeson-Forssman-Lehmann syndrome, seen in males, is characterized by severe cognitive deficit, epilepsy, hypogonadism, hypometabolism, marked obesity, infantile hypotonia and failure to thrive, and short stature. It can be distinguished by the severity of intellectual disability, the presence of nystagmus, and characteristic facial appearance with prominent superciliary ridges, ptosis, and deep-set eyes. Mutations in PHF6 are causative. Inheritance is X-linked. Heterozygous females who show manifestations of the disorder have skewed X-chromosome inactivation or a genomic deletion including PHG6.Alstrom syndrome is characterized by cone-rod dystrophy, early-onset obesity, progressive sensorineural hearing impairment, dilated cardiomyopathy (>60%), the insulin resistance syndrome/type 2 diabetes mellitus associated with acanthosis nigricans, and developmental delay (about 50%). Other endocrine abnormalities can include hypothyroidism and male hypogonadotropic hypogonadism. Urologic disorders of varying severity, characterized by detrusor-urethral dyssynergia, appear in females in their late teens. Severe renal disease is usually a late finding. Mutations in ALMS1 are found in 70%-80% of individuals of northern European descent, and about 40% of affected individuals worldwide.Cytogenetic abnormalities including the following:A “PWS-like phenotype” of syndromic obesity has been identified in individuals with an interstitial deletion of 6q16.2, which includes SIM1 [Varela et al 2005]. This deletion had been reported at least five times previously in syndromic obesity [Bonaglia et al 2008].There have been several reports of a Prader-Willi-like phenotype associated with 1p36 deletion, which includes hypotonia, developmental delay, obesity, hyperphagia, and behavioral problems.Reports of other cytogenetic anomalies in individuals with a PWS-like phenotype have included dup 3p25.3.3p26.2, dup Xq27.2-ter, del 3q27.3, del 6q16.2, and del 10q26.Features similar to those of PWS in the presence of joint contractures suggest Urban-Roger, Camera, or Vasquez syndromes, all of which are rare.Careful clinical evaluation by a medical geneticist or other trained diagnostician is useful to direct testing appropriately and may avoid the unnecessary expense of molecular testing for diagnoses that are less likely based on clinical findings.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementManagement of the manifestations of PWS is age-dependent and should include both addressing the consequences of the syndrome and anticipatory guidance. It is recommended that a team approach be used, if possible. Several approaches to management have been published recently [McCandless 2011, Cassidy & McCandless 2010, Eiholzer & Whitman 2004, Butler et al 2006, Goldstone et al 2008, Cassidy & Driscoll 2009, Cassidy et al 2012].Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Prader-Willi syndrome (PWS), the following evaluations are recommended:Assess newborns and young infants for sucking problems and failure to thrive.Regardless of age, measure and plot height and weight on either age-appropriate growth charts or charts developed for PWS [Butler et al 2006]. Calculation of BMI (weight in kg/height in m²) may be helpful.Assess development of infants; assess educational development of children including a speech evaluation.Refer for ophthalmologic evaluation if strabismus is present, and for assessment of visual acuity by age one year or at diagnosis if it is later.Assess males for the presence of cryptorchidism regardless of age.Assess children for hypothyroidism, especially those with prolonged failure to thrive, those with weight gain in the absence of increased food intake, and those with poor linear growth despite growth hormone treatment.Regardless of age, assess individuals for the presence of scoliosis clinically, and, if indicated, radiographically.
Note: Very obese individuals cannot be adequately assessed for scoliosis clinically; x-rays are necessary to establish the diagnosis.Assess for the presence of behavioral problems and obsessive-compulsive features after age two years, and for psychosis in adolescents and adults. If history reveals evidence of these problems, referral for more detailed assessment is indicated.Evaluate respiratory status and perform a sleep study regardless of age. These studies are specifically recommended prior to initiation of growth hormone therapy, along with assessment of the size of tonsils and adenoids, particularly in the obese individual.Treatment of ManifestationsA team approach to management is recommended [Eiholzer & Whitman 2004, Cassidy 2005].Special feeding techniques, including special nipples or gavage feeding, may be necessary for the first weeks to months of life to assure adequate nutrition and avoid failure to thrive.Early intervention in children under age three years, particularly physical therapy, may improve muscle strength and encourage achievement of developmental milestones. In older individuals, daily muscle training increases physical activity and lean body mass [Schlumpf et al 2006].Cryptorchidism may resolve spontaneously, even up to adolescence, but usually requires hormonal and surgical approaches; however, preservation of fertility is not an issue. Standard treatment is appropriate. Human chorionic gonadotropin treatment for infants with undescended testes should be considered as it can improve the size of the scrotal sac and improve surgical outcome [McCandless 2011; Angulo & Miller, unpublished data].Management of strabismus is as for any infant.When hyperphagia begins or weight centiles are increasing (often age 2-4 years), a program of a well-balanced, low-calorie diet, regular exercise, and close supervision to minimize food stealing should be instituted to prevent obesity and its consequences. The same program is appropriate if obesity is present at any time. Consultation with a dietician and close follow-up are usually necessary, and locking the kitchen, refrigerator, and/or cupboards is often needed once the child is able to open the refrigerator and cupboards. The energy requirement of people with PWS, which rarely exceeds 1000 to 1200 Kcal/day, should be considered in planning daily food intake. Assessment of adequacy of vitamin and mineral intake by a dietician, and prescription of appropriate supplementation, is indicated, especially for calcium and vitamin D.Growth hormone treatment normalizes height, increases lean body mass, decreases fat mass, and increases mobility, which are beneficial to weight management. Dose recommendations in young children are generally similar to those for individuals with isolated growth hormone deficiency, i.e., about 1 mg/m², but dose must be individualized as the child grows. It can be started in infancy or at the time of diagnosis. The adult dose of growth hormone is 20%-25% of the dose recommended in children.Controlled trials of growth hormone therapies have demonstrated significant benefit from infancy through adulthood [Lindgren et al 1997, Carrel et al 1999, Ritzén et al 1999, Eiholzer et al 2000, Mogul et al 2000, Carrel et al 2002, Carrel et al 2004, Eiholzer & Whitman 2004, Hoybye 2004, Whitman et al 2004, Hoybye et al 2005, Hoybye 2007, Myers et al 2007, Mogul et al 2008, Sode-Carlsen et al 2010].An increase in language and cognitive skills in treated infants [Myers et al 2007] and an improvement in mental speed and flexibility as well as motor performance in adults [Hoybye et al 2005] have been reported based on controlled trials.A review of the results of one to two years of growth hormone treatment among 328 children documented in the database of one pharmaceutical company indicated improved height velocity, particularly in prepubertal children, but no change in BMI [Craig et al 2006].Significantly greater adult height was demonstrated in 21 individuals treated long term versus 39 untreated individuals without an increase in adverse side effects [Angulo et al 2007].Improvements in cognition have been documented with growth hormone therapy in individuals with PWS [Osório 2012, Siemensma et al 2012].Although there was initial concern about growth hormone treatment contributing to scoliosis in PWS, recent studies show no difference in frequency or severity in those treated compared to those who were not treated [Nagai et al 2006, Angulo et al 2007].Initiate appropriate educational programming in children.Begin speech therapy for language delay and articulation abnormalities in infancy and childhood.Special education, either in an inclusion setting or in a self-contained classroom setting, is usually necessary during school age. An individual aide is helpful in assuring attendance to task. Social skills training groups have been beneficial.Behavioral disturbance should be addressed with behavioral management programs, including firm limit setting. While no medication is beneficial in managing behavior in all individuals with PWS, serotonin reuptake inhibitors have helped the largest proportion of affected teenagers and adults, particularly those with obsessive-compulsive symptoms [Brice 2000, Dykens & Shah 2003]. Psychosis is reported to respond well to selective serotonin reuptake inhibitors, but not to mood stabilizers [Soni et al 2007]. There are no well-designed studies of the effectiveness of treatment for psychosis in PWS [Ho & Dimitropoulos, 2010].Replacement of sex hormones produces adequate secondary sexual characteristics but is somewhat controversial because of the possible role of testosterone replacement in behavior problems in males and the role of estrogen replacement in the risk of stroke as well as hygiene concerns related to menstruation in females. Daily use of the testosterone patch or gel, or use of slow-release testosterone injection every three months, may avert exacerbation of behavioral problems by providing a more even blood level. Concern about osteoporosis should be considered in deciding about hormone replacement. Recent reports of fertility in four women with PWS raise the issue of need for birth control [Akefeldt et al 1999; Schulze et al 2001; Vats & Cassidy, unpublished data].Management of scoliosis, hip dysplasia, and complications of obesity is as in the general population.Decreased saliva production can be addressed with products developed for the treatment of dry mouth, including special toothpastes, gels, mouthwash, and gum.Disturbed sleep in children and adults should prompt a sleep study, as treatment may be available. Treatment depends on the cause and may include tonsillectomy and adenoidectomy and/or CPAP, as in the general population.There is a high prevalence of excessive daytime sleepiness, unrelated to the degree of sleep apnea, in individuals with PWS. Modafinil has been shown to be a safe and effective treatment for this condition [De Cock et al 2011].For adults with PWS, one successful living situation for behavior and weight management is a group home specially designated for individuals with PWS. Affected individuals generally require a sheltered employment environment.Issues of guardianship, wills, trusts, and advocacy should be investigated no later than adolescence.Prevention of Primary ManifestationsObesity may be prevented if the diet, exercise, and supervision program described in Treatment of Manifestations is instituted.If started at a young age, growth hormone treatment, along with good dietary control, may prevent or retard obesity and the high proportion of fat mass. It may also prevent development of the typical facial appearance.Prevention of Secondary ComplicationsDiabetes mellitus rarely occurs in the absence of obesity.Calcium and vitamin D supplementation may be beneficial, as low-calorie diets are often low in dairy products and osteoporosis has been documented in the majority of older children and adults with PWS.If osteoporosis develops, consider treatment with a bisphosphonate. Although no formal study exists, individuals with PWS tend to be very sensitive to medications of all kinds. Starting with lower doses is recommended.SurveillanceRecently health supervision guidelines from the American Academy of Pediatrics (AAP) were published [McCandless 2011; click for full text]. To assure appropriateness of exercise program and diet, including adequacy of vitamin and mineral intake, monitor height, weight, and BMI (weight in kg/height in m²):Every month in infancyEvery six months in the first decade of lifeAt least annually thereafterCryptorchidism can recur after orchidopexy; therefore, testicular position should be monitored.Evaluate for the presence of diabetes mellitus by standard methods (e.g., obtaining glycosylated hemoglobin concentration and/or glucose tolerance test) in anyone with significant obesity or rapid significant weight gain.Test annually for hypothyroidism, including free T4 and TSH levels. Obtain history of any sleep disturbance and obtain a sleep study if present.Monitor for development of scoliosis clinically or, in the presence of obesity, radiographically at least annually.Perform bone densitometry by DEXA to evaluate for possible osteoporosis every two years in adulthood.Obtain history for behavioral and psychiatric disturbance at least annually.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationTreatment of individuals with PWS with octreotide, a somatostatin agonist, decreased ghrelin concentrations but did not change eating behavior in several studies [Haqq et al 2003b, Tan et al 2004, De Waele et al 2008]. One study demonstrated decreased skin picking with topiramate treatment in some individuals [Shapira et al 2004] and other clinicians have anecdotally found similar results whereby about half of individuals with PWS who skin pick benefit from low-dose (25-50 mg daily) topiramate. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherNo medications are known to aid in controlling hyperphagia. Gastric bypass is contraindicated in PWS since it does not seem to correct the lack of satiety and will not prevent overeating. In addition, complication rates are high [Scheimann et al 2012].The only study of the use of coenzyme Q₁₀ for one year in children younger than age two years did not show improvement in body composition [Eiholzer 2004].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Prader-Willi Syndrome: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NamePWCRUnknown15q11​.2UnknownData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Prader-Willi Syndrome (View All in OMIM) View in own window 137142GAMMA-AMINOBUTYRIC ACID RECEPTOR, ALPHA-5; GABRA5 137192GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3 176270PRADER-WILLI SYNDROME; PWS 182279SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE N; SNRPN 600161PRADER-WILLI/ANGELMAN REGION TRANSCRIPT 1 600233GAMMA-AMINOBUTYRIC ACID RECEPTOR, GAMMA-3; GABRG3 601491IMPRINTED IN PRADER-WILLI SYNDROME; IPW 601623UBIQUITIN-PROTEIN LIGASE E3A; UBE3A 602117NECDIN; NDN 603856MAKORIN 3; MKRN3 603857MKRN3 ANTISENSE RNA; MKRN3AS 605283MAGE-LIKE 2; MAGEL2 605436SMALL NUCLEOLAR RNA, C/D BOX, 116-1; SNORD116-1 605837HECT DOMAIN AND RCC1-LIKE DOMAIN 2; HERC2 605855ATPase, CLASS V, TYPE 10A; ATP10A 609837SMALL NUCLEOLAR RNA, C/D BOX, 115-1; SNORD115-1 610922NUCLEAR PORE ASSOCIATED PROTEIN 1; NPAP1 611215PRADER-WILLI REGION NONCODING RNA 1; PWRN1 611409OCA2 GENEMolecular Genetic PathogenesisThe PWS region is localized to a 5-6 Mb genomic region on the proximal long arm of chromosome 15 (15q11.2-q13) (Figure 2). It lies within a smaller 2.5-Mb differentially imprinted region. PWS is a contiguous gene disorder, since studies thus far indicate that the complete phenotype is due to the loss of expression of several genes. It is also an example of an imprinted condition, since the expression of relevant genes in the 15q11.2-q13 region is dependent on parental origin [Glenn et al 1997, Bittel et al 2006].The genomic and epigenetic changes causing PWS all lead to a loss of expression of the normally paternally expressed genes on chromosome 15q11.2-q13. Absence of the paternally inherited copy of these genes, or failure to express them, causes total absence of expression for those genes in the affected individual because the maternal contribution for these genes has been programmed by epigenetic factors to be silenced [Glenn et al 1997, Cassidy & Driscoll 2009]. Conversely, a loss of expression of preferentially maternally expressed UBE3A in this region by several different possible mechanisms leads to Angelman syndrome [Lossie et al 2001, Williams et al 2010].The 15q11.2-q13 region can be roughly divided into four distinct regions which are delineated by three common deletion breakpoints [Christian et al 1999] lying within segmental duplications [Amos-Landgraf et al 1999] (see Figure 2): A proximal non-imprinted region between the two common proximal breakpoints (BP1 and BP2) containing four biparentally expressed genes, NIPA1, NIPA2, CYF1P1, and GCP5 [Chai et al 2003]The “PWS paternal-only expressed region” containing five polypeptide coding genes (MKRN3, MAGEL2, NECDIN, and the bicistronic SNURF-SNRPN); C15orf2 (an intronless gene that is biallelically expressed in testis, but only expressed from the paternal allele in brain); a cluster of C/D box small nucleolar RNA genes (snoRNAs) and several antisense transcripts (including the antisense transcript to UBE3A) The “Angelman syndrome (AS) region” containing the preferentially maternally expressed genes UBE3A and ATP10AA distal non-imprinted region containing a cluster of 3 GABA receptor genes, the gene for oculocutaneous albinism type 2 (OCA2), HERC2 and the common distal breakpoint (BP3) Central to the PWS region is SNURF-SNRPN. It is a bicistronic gene encoding two different proteins. At the 5’ end of SNURF-SNRPN is a CpG island encompassing the promoter, exon 1 and intron 1. This is a differentially methylated region which is unmethylated on the paternally inherited expressed allele and methylated on the maternally inherited repressed allele [Glenn et al 1996]. The CpG island and exon 1 are within the 4.3 kb smallest region of deletion overlap (SRO) for the paternal PWS imprinting center (IC) [Ohta et al 1999]. SNURF-SNRPN also serves as the host for the six snoRNA genes located telomerically which are regulated by the expression of SNURF-SNRPN. The UBE3A antisense transcript also arises from transcription of SNURF-SNRPN and is thought to lead to repression of the paternally inherited UBE3A in humans and mice [Cavaillé et al 2000, Chamberlain & Brannan 2001, Runte et al 2001].The snoRNAs are present in single copy except for SNORD116 (previously named HBII-85) and SNORD115 (previously named HBII-52), which are present in 29 and 42 copies, respectively. It is thought that the snoRNAs are probably involved in the modification of mRNA by alternative splicing and that each snoRNA gene may have multiple targets. However, at the present time only one target for a snoRNA gene (i.e., SNORD115) has been found and that is the serotonin 2C receptor [Kishore & Stamm 2006]. No targets have yet been found for SNORD116.The exact function of each of the genes in determining the PWS phenotype remains to be elucidated, although possible insight has been gained by work with mouse models by multiple investigators. No single gene mutation that will explain all the features of PWS has been found in humans, unlike the situation in AS where single gene mutations of UBE3A fulfill all the major clinical criteria for AS [Lossie et al 2001, Williams et al 2010]. However, a “key” region to explain much of the PWS phenotype has been narrowed to the SNORD116 snoRNA gene cluster by several unique deletion and translocation families [reviewed by Buiting 2010]. A crucial role for the SNORD115 locus was eliminated by an AS family with a familial microdeletion that included the entire SNORD115 cluster and the UBE3A locus [Runte et al 2005]. There was no obvious phenotype when this microdeletion was passed paternally, but it resulted in AS when inherited maternally.Critical region. PWS/AS critical regionNormal allelic variants. The following genes have been mapped within the PWS/AS region:SNURF-SNRPN is a complex bicistronic gene encoding two different proteins. Exons 4-10 were described first and encode the protein SmN, which is a spliceosomal protein involved in mRNA splicing [Glenn et al 1996]. SNURF is encoded by exons 1-3 and produces a polypeptide of unknown function [Gray et al 1999]. It also serves as the host for the six snoRNA genes located telomerically which are regulated by the expression of SNURF-SNRPN. IPW is thought to be an RNA transcript only, as it does not encode a protein.PAR1, PAR4, PAR5, and PAR7 are anonymous transcripts.OCA2 (previously known as P), codes for tyrosinase-positive albinism; its deletion is associated with the hypopigmentation seen in one third of individuals with PWS.GABRB3, GABRA5, and GABRG3, all GABA-receptor subunit genesUBE3A (previously known as E6AP) is associated with AS.ATP10A, a maternally expressed gene, is within the most common interval of deletion responsible for AS.HERC2 and multiple duplications occur at the common deletion breakpoints.NECDIN (NDN) encodes a DNA binding protein. A NDN knockout mouse model has indicated that NDN mediates intracellular processes essential for neurite outgrowth, and loss of necdin impinges on axonal outgrowth [Lee et al 2005]. A mouse Necdin knockout model has been reported with similar defects to individuals with PWS and indicates that Necdin is an antiapoptotic or survival factor in the early development of the nervous system [Andrieu et al 2006].MAGEL2, an intronless gene in proximity to the NDN locus, is transcribed only by the paternal allele and expressed predominantly in the brain. Studies of Magel2-null mice have demonstrated several findings that are associated with key aspects of PWS, including neonatal growth retardation, excessive weight gain after weaning, and increased adiposity with altered metabolism in adulthood [Lee et al 2005, Bischof et al 2007]. It has been implicated in circadian rhythm in mice [Kozlov et al 2007].MKRN3 (Markorin 3, ZNF127) is a zinc finger protein expressed only from the paternal chromosome.C15orf2 is an intronless gene that is biallelically expressed in adult testis but monoallelically expressed in fetal brain.PWRN1, expressed in testis, demonstrates lower expression in prostate, heart, kidney, liver, lung, skeletal muscle, trachea, spinal cord, and fetal brain; shown to have monoallelic expression in the fetal brain.snoRNA HBII-85 (SNORD 116). Two lines of evidence suggest that snoRNA HBII-85 cluster is causative. Balanced translocations that preserve the expression of SNURF-SNRPN and centromeric genes that separate the SNORD 116 cluster from its promoter cause Prader-Willi syndrome. More recently a microdeletion of the SNORD 116 cluster has been reported in three individuals with many PWS features (see Pathologic allelic variants). These two lines of evidence suggest that a deficiency of the SNORD 116 snoRNA leads to key features seen in PWS.Several other imprinted genes and transcripts of unknown function have been identified.Pathologic allelic variants. Most cases of PWS result from an interstitial microdeletion of the paternally inherited 15q11.2-q13 region [Ledbetter et al 1981, Butler & Palmer 1983, Glenn et al 1997]. Deletions account for 65%-75% of individuals with PWS. The vast majority of individuals with deletions have one of two common proximal breakpoints (BP1 or BP2) and a common distal breakpoint (BP3) (see Figure 2) [Christian et al 1995, Amos-Landgraf et al 1999]. These recurrent common interstitial deletions measure about 5-6 Mb in size and are caused by the presence of multiple copies of tandemly repeated sequences at the common breakpoints (BP1, BP2 and BP3) flanking the deleted region. These low copy repeat sequences stretch for about 250-400 kb and can cause non-homologous pairing and aberrant recombination of the 15q11.2-q13 region during meiosis, leading to deletions (causing PWS or AS depending on parental origin), duplications (both maternal and paternal), triplications, and inverted dup (15) [Robinson et al 1998, Amos-Landgraf et al 1999, Boyar et al 2001, Maggouta et al 2003, Depienne et al 2009]. In addition, about 8% of those had unique or atypical-sized deletions (i.e., not type 1 or 2) from a variety of etiologies, including an unbalanced translocation [Kim et al 2012]. A deletion that is smaller or larger than typically seen in PWS may affect the phenotype. Small deletions of the promoter region and the proximal upstream region of SNRPN (including the putative imprinting control element) have been identified in individuals with PWS who have maternal-specific DNA methylation patterns, but who have neither the usual large paternally derived deletion of the PWS/AS region nor maternal UPD. This pattern is considered an ID via an IC microdeletion.Other individuals have biparental inheritance, but maternal-only DNA methylation patterns in this region without detectable abnormalities in the SRO for the IC. These individuals are considered to have an ID by an epimutation.Recently there have been three separate reports of three different individuals with overlapping microdeletions (175 to 236 kb) that all encompass the SNORD116 gene cluster [Sahoo et al 2008, de Smith et al 2009, Duker et al 2010]. All three have multiple clinical features typical of PWS including neonatal hypotonia, infantile feeding problems, rapid weight gain by two years of age, hyperphagia, hypogonadism, developmental delay/intellectual disability, and speech and behavioral problems. However, these three individuals also have features not typical of classical PWS, including tall stature as a child, large head circumference, lack of a “PWS facial gestalt”, and hand features not typical of PWS. Furthermore, rigorous neurobehavioral studies have not been performed to determine if these individuals have the typical PWS behavioral phenotype. Nonetheless, it is clear from these studies that absence of the paternally derived SNORD116 cluster plays a major role in the PWS phenotype.Normal gene product. The only identified protein products are those for SNRPN and MKRN3. SNRPN is a small nuclear ribonucleoprotein involved in alternative mRNA splicing.Abnormal gene product. UnknownImprinting. Several of the genes in the PWS region (SNURF-SNRPN, MKRN3, NDN, MAGEL2, C15orf2, PWRN1) are subject to genomic imprinting, thus accounting for the fact that the PWS phenotype results only when the paternally contributed PWS region is absent. DNA methylation, which is involved in the process of genomic imprinting, has been demonstrated for several of the genes identified within the PWS region [Glenn et al 1996, Glenn et al 1997, MacDonald & Wevrick 1997]. Upstream of SNRPN, very small deletions of the putative imprinting control element for the region have been identified in a few individuals with PWS who have maternal-specific DNA methylation patterns but have neither the usual large paternally derived deletion of the PWS/AS region nor maternal UPD [Saitoh et al 1997, Ohta et al 1999]. Other individuals demonstrate sporadic imprinting defects that are epimutations [Buiting et al 1998, Buiting et al 2003].