Genetic test panel for Prader-Willi syndrome

Defects in 15q11.2-q13 consistent with PWS	Percent of PWS cases	Molecular findings	Risk of recurrence in future siblings (percent)	Parental follow-up testing
Deletions of PWS-critical region on paternal 15q11-q13	65 to 75	Methylation studies abnormal Deletion analysis abnormal (CMA)*	<1^¶	Consider paternal karyotype to look for chromosomal rearrangement
Maternal uniparental disomy	20 to 30^Δ	Methylation studies abnormal Deletion analysis normal (CMA*), and either: CMA with 15q11.2 homozygosity^◊, or Uniparental disomy analysis abnormal^§ (ie, maternal uniparental inheritance)	<1^¶	Karyotype of the proband to rule out Robertsonian translocation (rare)
Imprinting center defects
Epimutations without deletion	2	Methylation studies abnormal Deletion analysis normal (CMA*) Uniparental disomy analysis normal^§ (ie, biparental inheritance) DNA sequence analysis reveals no deletion	<1
Deletion	<0.5	Above, except that DNA sequence analysis reveals deletion	Up to 50	Paternal sequencing (SNRPN gene) for deletion

Molecular defects associated with PWS and associated risk for recurrence in siblings of an affected child^[1].

PWS: Prader-Willi syndrome; FISH: fluorescence in situ hybridization; CMA: chromosomal microarray; DNA: deoxyribonucleic acid; SNP: single-nucleotide polymorphism.

* FISH also may be used for deletion analysis, but the analysis is less detailed than CMA.

¶ Rare defects with a substantial risk of recurrence in a sibling are chromosomal rearrangement (<1% of PWS cases) and maternal uniparental disomy with predisposing parental translocation or marker chromosome (<1% of PWS cases).

Δ The risk of maternal uniparental disomy probably rises with maternal age^[2,3].

◊ Rarely, balanced or unbalanced chromosomal translocations involving chromosome 15 may result in PWS. Methylation is consistent with the presence of only the maternal allele in these cases^[2].

§ Uniparental disomy analysis is ideally performed with parental karyotype but can also be done with microsatellite probes or SNPs of parents and child.

References:

Strom SP, Hossain WA, Grigorian M, et al. A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics. Front Genet 2021; 12:608889.
Klein OD, Cotter PD, Albertson DG, et al. Prader-Willi syndrome resulting from an unbalanced translocation: characterization by array comparative genomic hybridization. Clin Genet 2004; 65:477.
Lionti T, Reid SM, White SM, Rowell MM. A population-based profile of 160 Australians with Prader-Willi syndrome: trends in diagnosis, birth prevalence and birth characteristics. Am J Med Genet A 2015; 167A:371.
Whittington JE, Butler JV, Holland AJ. Changing rates of genetic subtypes of Prader-Willi syndrome in the UK. Eur J Hum Genet 2007; 15:127.

Adapted from: Driscoll DJ, Miller JL, Schwartz S, and Cassidy SB. Prader-Willi Syndrome (1998 Oct 6 [Updated 2017 Dec 14]). In: Adam MP, Everman DB, Mirzaa GM, et al, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1330/ (Accessed on September 14, 2022).

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Genetic test panel for Prader-Willi syndrome