The dilemma of diagnostic testing for Prader-Willi syndrome

Smith, Arabella; Hung, Dorothy

doi:10.21037/tp.2016.07.04

Cited by 30 publications

(25 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As mentioned by Smith and Hung (Smith & Hung, ), there are some issues that must be considered with regard to clinical and laboratory diagnosis: (I) Separate the few PWS patients from the vast majority of laboratory references that fall into the differential diagnosis at birth and thereafter (Dulka, Choudhary, Methratta, & Fortuna, ); (II) When PWS is diagnosed, it is necessary to separate individuals at risk for high recurrence (IC deletion) from those with low risk of recurrence (deletions and UPD); (III) To make the test as user‐friendly as possible—it is difficult to get blood or other tissue from the patient, and the family is not always available; and (IV) Beware of the impact of the cost of the exam in the public health system.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormalities are occurring at the paternal allele on chromosome 15q11‐q13 results in PWS (Sun et al., ), while abnormalities in the maternal copy of the same region cause AS. The genetic mechanisms leading to PWS include (1) deletion of the syndrome‐associated region (~75%), (2) uniparental disomy (UPD) (~25%), or (3) imprinting center defect (IC) (~1% of PWS) (Smith & Hung, ). The frequency of rearrangements occurs in ~5% of the individuals and can be balanced or unbalanced (Kuslich, Kobori, Mohapatra, Gregorio‐King, & Donlon, ; Reeve et al., ; Robinson et al., ; Smith et al., ; Yip, ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A rapid and accurate methylation‐sensitive high‐resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients

Ferreira¹,

Cunha²,

Gomes³

et al. 2019

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background Prader Willi (PWS) and Angelman (AS) syndromes are rare genetic disorders characterized by deletions, uniparental disomy, and imprinting defects at chromosome 15. The loss of function of specific genes caused by genetic alterations in paternal allele causes PWS while the absence in maternal allele results AS. The laboratory diagnosis of PWS and AS is complex and demands molecular biology and cytogenetics techniques to identify the genetic mechanism related to the development of the disease. The DNA methylation analysis in chromosome 15 at the SNURF‐SNRPN locus through MS‐PCR confirms the diagnosis and distinguishes between PWS and AS. Our study aimed to establish the MS‐PCR technique associated with High‐Resolution Melting (MS‐HRM) in PWS and AS diagnostic with a single pair of primers. Methods We collected blood samples from 43 suspected patients to a cytogenetic and methylation analysis. The extracted DNA was treated with bisulfite to perform comparative methylation analysis. Results MS‐HRM and MS‐PCR agreed in 100% of cases, identifying 19(44%) PWS, 3(7%) AS, and 21(49%) Normal. FISH analysis detected four cases of PWS caused by deletions in chromosome 15. Conclusion The MS‐HRM showed good performance with a unique pair of primers, dispensing electrophoresis gel analysis, offering a quick and reproducible diagnostic.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A rapid and accurate methylation‐sensitive high‐resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients

Ferreira¹,

Cunha²,

Gomes³

et al. 2019

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…The hypothalamic dysfunction observed in PWS may be the basis of several symptoms (such as hypotonia, developmental delay or obesity) that overlaps features of other conditions on clinical grounds, like normal obesity and intellectual disability (42).…”

Section: Molecular Genetics and Diagnosticmentioning

confidence: 99%

Genotype-Phenotype Relationships and Endocrine Findings in Prader-Willi Syndrome

Costa¹,

Ferreira²,

Cintra³

et al. 2019

Front. Endocrinol.

View full text Add to dashboard Cite

Prader-Willi syndrome (PWS) is a complex imprinting disorder related to genomic errors that inactivate paternally-inherited genes on chromosome 15q11-q13 with severe implications on endocrine, cognitive and neurologic systems, metabolism, and behavior. The absence of expression of one or more genes at the PWS critical region contributes to different phenotypes. There are three molecular mechanisms of occurrence: paternal deletion of the 15q11-q13 region; maternal uniparental disomy 15; or imprinting defects. Although there is a clinical diagnostic consensus criteria, DNA methylation status must be confirmed through genetic testing. The endocrine system can be the most affected in PWS, and growth hormone replacement therapy provides improvement in growth, body composition, and behavioral and physical attributes. A key feature of the syndrome is the hypothalamic dysfunction that may be the basis of several endocrine symptoms. Clinical and molecular complexity in PWS enhances the importance of genetic diagnosis in therapeutic definition and genetic counseling. So far, no single gene mutation has been described to contribute to this genetic disorder or related to any exclusive symptoms.Here we proposed to review individually disrupted genes within the PWS critical region and their reported clinical phenotypes related to the syndrome. While genes such as MKRN3, MAGEL2, NDN, or SNORD115 do not address the full spectrum of PWS symptoms and are less likely to have causal implications in PWS major clinical signs, SNORD116 has emerged as a critical, and possibly, a determinant candidate in PWS, in the recent years. Besides that, the understanding of the biology of the PWS SNORD genes is fairly low at the present. These non-coding RNAs exhibit all the hallmarks of RNA methylation guides and can be incorporated into ribonucleoprotein complexes with possible hypothalamic and endocrine functions. Also, DNA conservation between SNORD sequences across placental mammals strongly suggests that they have a functional role as RNA entities on an evolutionary basis. The broad clinical spectrum observed in PWS and the absence of a clear genotype-phenotype specific correlation imply that the numerous genes involved in the syndrome have an additive deleterious effect on different phenotypes when deficiently expressed.

show abstract

“…Vizsgálatunk alapján a HRM megfelelő elsődleges genetikai vizsgálat lehet, amennyiben az MS-MLPA technikai vagy anyagi okok miatt nem érhető el (2. táblázat) [16][17][18].…”

Section: Következtetésunclassified

Elsődleges genetikai vizsgálat Prader–Willi-szindróma igazolására

et al. 2018

View full text Add to dashboard Cite

Bevezetés: A nemzetközi szakirodalmi adatok alapján az SNRPN génlocus promoter régiójának DNS-metilációs vizsgálata jelenleg a legérzékenyebb és leghatékonyabb kezdeti lépés a Prader-Willi-szindróma-gyanús betegek genetikai vizsgálatakor. Célkitűzés: Célunk egy egyszerű, megbízható, könnyen hozzáférhető, elsődlegesen diagnosztikus, DNS-metiláción alapuló eljárás kidolgozása volt Prader-Willi-szindróma igazolására. Módszer: Vizsgálatunk során az általunk módosított, költséghatékony, metilációszenzitív, nagy felbontású olvadás-pont-elemzéses technikát hasonlítottuk össze a leginkább elterjedt, költséges metilációspecifikus multiplex ligatiofüggő próbaamplifikációs technikával. Klinikailag a Prader-Willi-szindróma több tünetét mutató 17 gyermek DNSmetilációs vizsgálatát végeztük el saját tervezésű primerekkel: biszulfitszekvenáló polimeráz-láncreakció, metilációszenzitív nagy felbontású olvadáspont-elemzés és kontrollként metilációspecifikus multiplex ligatiofüggő próbaamplifikáció történt. Eredmények: A metilációszenzitív nagy felbontású olvadáspont-elemzés és a metilációspecifikus multiplex ligatiofüggő próbaamplifikáció eredményei minden esetben megegyeztek. A 17 esetből 6 esetben igazolódott a Prader-Williszindróma. Következtetés: Az általunk használt DNS-metiláción alapuló módszer, amelyben együttesen alkalmaztunk egyedi tervezésű primereket és módosított biszulfitszekvenáló polimeráz-láncreakciót, egyszerű, gyors, megbízható és haté-kony vizsgálatnak bizonyult a Prader-Willi-szindróma elsődleges igazolására. Orv Hetil. 2018; 159(2): 64-69. Kulcsszavak: Prader-Willi-szindróma, molekuláris genetika, DNS-metiláció Rapid first-tier genetic diagnosis in patients with Prader-Willi syndromeIntroduction: According to the international literature, DNA methylation analysis of the promoter region of SNRPN locus is the most efficient way to start genetic investigation in patients with suspected Prader-Willi syndrome. Aim: Our aim was to develop a simple, reliable first-tier diagnosis to confirm Prader-Willi syndrome, therefore to compare our self-designed simple, cost-efficient high-resolution melting analysis and the most commonly used methylation-specific multiplex ligation-dependent probe amplification to confirm Prader-Willi syndrome. Method: We studied 17 clinically suspected Prader-Willi syndrome children and their DNA samples. With self-designed primers, bisulfite-sensitive polymerase chain reaction, high-resolution melting analysis and, as a control, methylation-specific multiplex ligation-dependent probe amplification were performed. Results: Prader-Willi syndrome was genetically confirmed in 6 out of 17 clinically suspected Prader-Willi syndrome patients. The results of high-resolution melting analysis and methylation-specific multiplex ligation-dependent probe amplification were equivalent in each case. Conclusion: Using our self-designed primers and altered bisulfite-specific PCR conditions, high-resolution melting analysis appears to be a simple, fast, reliable and effective method for primarily proving or e...

show abstract

The dilemma of diagnostic testing for Prader-Willi syndrome

Cited by 30 publications

References 51 publications

A rapid and accurate methylation‐sensitive high‐resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients

A rapid and accurate methylation‐sensitive high‐resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients

Genotype-Phenotype Relationships and Endocrine Findings in Prader-Willi Syndrome

Elsődleges genetikai vizsgálat Prader–Willi-szindróma igazolására

Contact Info

Product

Resources

About