Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next‐generation whole‐exome sequencing

Hartin, Samantha N.; Hossain, Waheeda A.; Francis, David; Godler, David E.; Barkataki, Sangjucta; Butler, Merlin G.

doi:10.1002/mgg3.575

Cited by 16 publications

(18 citation statements)

References 24 publications

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“…Additionally, hormonal-mediated gender influences or differential expression in the brain should be examined for dysregulation in ASD including methylation status of brain-expressed genes on the X chromosome and interaction with autosomal genes (e.g., X-linked FMR1 gene causing fragile X syndrome [116] and CYFIP1 gene at 15q11.2 involved with coding transporter for FMR1 protein [117]). These investigations will require more specialized methods with increased sensitivity such as droplet digital PCR [118].…”

Section: Future Directionsmentioning

confidence: 99%

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD)

Genovese

Butler

2020

IJMS

Self Cite

157

107

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Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity.

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Section: Future Directionsmentioning

confidence: 99%

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD)

Genovese

Butler

2020

IJMS

Self Cite

157

107

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“…However, early diagnosis combined with multidisciplinary care favourably influences the course of PWS 17 ; therefore, the diagnosis should be confirmed early during the neonatal period, 18 with the support of genetic testing development. 19 In this context, early GH treatment has beneficial outcomes on, for example, height, body composition, endurance and sense of wellbeing [20][21][22] ; furthermore, early treatment with recombinant GH positively affects the HRQoL of patients with PWS 23 and caregivers. 24 25 The social, relational, emotional and existential aspects of PWS remain profoundly unknown, and the debate within Italian clinical and social communities has been poor: the WHO has stressed the importance of researching the measurable dimensions of HRQoL and-more broadly-illness experiences in leading clinical and social practice and recommends using narrative research.…”

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Caring and living with Prader-Willi syndrome in Italy: integrating children, adults and parents’ experiences through a multicentre narrative medicine research

et al. 2020

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ObjectivesPrader-Willi syndrome (PWS) significantly impacts health-related quality of life; however, its relational and existential aspects remain unknown in Italian clinical and social debate. The project aimed to investigate the impact of PWS on illness experience through narrative medicine (NM) to understand the daily life, needs and resources of patients with PWS and their caregivers, and to furnish insights for clinical practice.Design and settingThe project involved 10 medical centres of the Italian Network for Rare Diseases and PWS family associations and targeted underage and adult patients with PWS and their caregivers. Written interviews, composed by a sociodemographic survey and a narrative, were collected through the project’s website. Three dedicated illness plots employed evocative and open words to facilitate individual expression and to encourage reflection. Narratives were analysed through NVivo software. Researchers discussed the results with the project’s steering committee.ParticipantsTwenty-one children and adolescents and 34 adults with PWS joined the project, as well as 138 caregivers. A PWS diagnosis or the caregiving of a patient with PWS older than 5 years represented the eligibility criteria, as well as the willingness to share their illness experience by writing and the ability to communicate in Italian.ResultsThe analysis of narratives led to understanding the PWS social and relational issues concerning diagnosis and current management, PWS daily experiences and social contexts, PWS implications in the working sphere and participants’ future perspectives. Narratives demonstrated that PWS management affects relationships and work-life balance and that social stigma remains present.ConclusionThe project represented the first effort to investigate the impact of PWS on illness experience in Italy through NM while considering the perspectives of patients with PWS and their caregivers. The findings indicated that a multiprofessional approach is fundamental to ensure adequate treatment and provided elements for its improvement.

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“…Most PWS patients (65-75%) present a 5-6 Mb deletion at 15q11-q13 from the paternal origin (16,49). There are two proximal breakpoints and a common distal breakpoint (Figure 1), these regions are flanked by low copy repeat sequences that predispose to abnormal chromosomal pairing and uneven crossing-over, resulting in errors during meiosis (50,51). Maternal Uniparental Disomy (mDUP) occurs when both chromosomes 15 are inherited from the mother and accounts for ∼20-30% of cases, being associated with advanced maternal age (9,15).…”

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.

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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.

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Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next‐generation whole‐exome sequencing

Cited by 16 publications

References 24 publications

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD)

Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD)

Caring and living with Prader-Willi syndrome in Italy: integrating children, adults and parents’ experiences through a multicentre narrative medicine research

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

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