Overview of genetic testing in Prader-Willi syndrome

Figures & data

Figure 1. Overview of the critical region for PWS. Blue spots represent biallelically expressed genes, orange boxes/vertical lines represent paternally expressed genes, and green vertical lines represent maternally expressed genes. It is adapted from [6].

Table 1. Genotypes and phenotypes in PWS.

Genotypes	Incidence	Mechanism	Phenotypes
Deletions	70–75%	Type I: BP1-BP3	1. Type I deletion present more behavior and cognitive problems than type II 2. Atypical deletion leads to a milder or more severe phenotype than the typical deletion 3. More frequently present feeding problems, hypopigmentation, sleep disturbance and speech articulation defects than UPD
		Type II: BP2-BP3
		Atypical deletion
mUPD	25–30%	Maternal heterodisomy	1. Highly associated with advanced maternal age 2. Higher verbal IQ scores and better social skills but more prone to autism
		Maternal isodisomy
		Segmental isodisomy
ID	about 3%	Epimutation	1. ID epimutation has a small recurrence risk 2. ID microdeletion has a 50% recurrence risk 3. The phenotype is similar to mUPD15
		Microdeletion in the imprinting center
Rearrangements	<1%	Unbalanced Chr 15 rearrangements cause deletion	1. Possibly have a 50% recurrence risk 2. Have a higher risk of having other genetic diseases
		Balanced Chr 15 rearrangements

Table 2. Consensus clinical diagnostic criteria for PWS.

	Major criteria (1 point each)	Minor criteria (1/2 point each)	Supportive Findings (not score)
1	Hypotonia with poor suck	Decreased fetal movement/infantile lethargy/weak cry	High pain threshold
2	Feeding problems and poor weight gain/failure to thrive	Characteristic behavior problems	Decreased vomiting
3	Excessive weight gain at 1–6 years and central obesity	Sleep disturbance	Temperature instability/altered temperature sensitivity
4	Characteristic facial features	Short stature	Scoliosis/kyphosis
5	Hypogonadism	Hypopigmentation	Early adrenarche
6	Global developmental delay	Small hands/feet	Osteoporosis
7	Hyperphagia	Narrow hands with straight ulnar border	Unusual skill
8	Abnormality of the Prader-Willi chromosome region	Eye abnormalities	Normal neuromuscular studies
9		Thick viscous saliva
10		Speech articulation defects
11		Skin picking
For children ≤3 years of age: 5 points are necessary, and at least 4 points come from major criteria. For children >3 years of age: 8 points are required, and at least 5 points come from major criteria.

It is adapted from Yang-Li D et al [20].

Table 3. Revised criteria to prompt DNA testing for PWS.

Age at Assessment	Clinical Features of Prompt DNA Testing
<2 years	1. Hypotonia with poor suck
2–6 years	1. Hypotonia with a history of poor suck 2. Developmental delay
6–12 years	1. History of hypotonia with poor suck 2. Developmental delay 3. Excessive eating with central obesity
≥13 years	1. Cognitive impairment 2. Excessive eating with central obesity 3. Hypothalamic hypogonadism/typical behavior problems

It is adapted from Gunay-Aygun et al [11].

Table 4. Advantages and limitations of PWS diagnosis.

	Uses	Limitations
Cytogenetic diagnosis
FISH	Can detect deletion and chromosomal rearrangement, could detect about 65–75% of PWS	Cannot distinguish normal and UPD, ID Cannot distinguish PWS and AS deletions Cannot give information about the whole PWS critical region and the other chromosomes
CMA (CGH+SNP)	Can detect deletion (including deletion size), UPD isodisomy and additional chromosomal anomalies and could detect about 80–90% of PWS	Cannot identify chromosomal rearrangement Cannot distinguish UPD heterodisomy and ID epimutation Cannot distinguish PWS and AS deletions
Molecular genetic diagnosis
MS-PCR	Can detect more than 99% of PWS (including deletion, UPD and ID)	Cannot distinguish the underlying genetic mechanism Cannot identify chromosomal rearrangement
MS-MLPA	Can detect more than 99% of PWS (including deletion, UPD and ID) Can distinguish PWS and AS deletion deletion Can distinguish deletion and nondeletion Can distinguish Type I and Type II deletion	Cannot distinguish UPD and ID Cannot identify chromosomal rearrangement
MS-MA/MS-HRM	Can detect deletion, UPD and ID Can distinguish deletion and nondeletion Can decrease PCR contamination risk and dispense electrophoresis gel analysis	Cannot distinguish the underlying genetic mechanism The melting curve that cannot be unambiguously assigned should be further investigated
Pyrosequencing	Can detect including deletion, UPD and ID Can quantify SRNPN gene Methylation Can detect PWS with mosaic mUPD	Cannot distinguish the underlying genetic mechanism Affected by DNA centration, PCR amplification bias, and bisulfite treatment
MSA	Can detect deletion (especially for microdeletion) and UPD heterodisomy	Not a first-line test, performed after methylation analysis diagnoses PWS Cannot distinguish UPD isodisomy and ID Should require both proband and parents’ DNA samples

Figure 2. Genetic testing strategies for the Prader-Willi syndrome.

Yang L, Shu X, Mao S, et al. Genotype–Phenotype Correlations in Angelman Syndrome. Genes. 2021;12(7):987. doi: 10.3390/genes12070987

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Yang-Li D, Fei-Hong L, Hui-Wen Z, et al. Recommendations for the diagnosis and management of childhood Prader-Willi syndrome in China. Orphanet J Rare Diseases. 2022 Jun 13;17(1):221. doi: 10.1186/s13023-022-02302-z

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Gunay-Aygun M, Schwartz S, Heeger S, et al. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics. 2001 Nov;108(5):E92. doi: 10.1542/peds.108.5.e92

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