A next generation sequencing gene panel for use in the diagnosis of anorexia nervosa

Ceccarini, Maria Rachele; Precone, Vincenza; Manara, Elena; Paolacci, Stefano; Maltese, Paolo Enrico; Benfatti, Valentina; Dhuli, Kristjana; Donato, Kevin; Marceddu, Giuseppe; Chiurazzi, Pietro; Ragione, Laura Dalla; Beccari, Tommaso; Bertelli, Matteo

doi:10.1007/s40519-021-01331-0

Cited by 12 publications

(10 citation statements)

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“…Researchers reported that AN runs in family in relation with genetic factors. Lombardi et al in 2019 and Ceccarrini et al, 2021 sequenced some families (with AN) and found signi cant association of NNAT (neuronatin) gene variants (single nucleotide polymorphism -SNP) in an identi ed population with AN [2,10]. Lombardi et al, suggested that the constitutional reduced level of NNAT-α isoform in brain and in adipocytes from inclusive study subjects may predispose to AN [2].…”

Section: Discussionmentioning

confidence: 99%

“…They correlated the dysregulation of NNAT gene (α isoform) expression could be linked with the propensity of having AN [2]. Ceccarrini et al in 2021 reported the role of con rmation of the involvement of the NNAT gene in the pathogenesis of AN [10]. In coherence with this posit we have attempted to further examine NNAT's changing expression in the brain as a pivotal nding and relate its role in development of AN.…”

Section: Introductionmentioning

confidence: 97%

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In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa

et al. 2022

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Purpose Increase susceptibility towards Anorexia nervosa (AN) was reported with reduced levels of NNAT gene. We sought to investigate the most pathogenic rare-coding missense mutations (nsSNPs) of NNAT and their potential damaging impact on protein function through transcript level sequence and structure based in silico approaches. Methods Gene sequence, SNPs of NNAT was retrieved from public databases and the putative post-translational modi cation (PTM) sites were analyzed. Distinctive in silico algorithms were recruited for transcript level SNPs analyses and to characterized high risk rare-coding nsSNPs along with their impact on protein stability function. Ab initio 3D-modeling of wild-type, alternate model prediction for most deleterious nsSNP, validation and recognition of druggable binding pockets were also performed. AN 3D therapeutic compounds followed rule of drug-likeness were docked with most pathogenic variant of NNAT to estimate the drugs' binding free energies.Results Conclusively, 10 transcripts (201-205) based nsSNPs from 3 rare-coding missense variants i.e., rs539681368, rs542858994, rs560845323 out of 840 exonic SNPs were identi ed. Transcript based functional impact analyses predicted rs539681368 (C30Y) from NNAT-204 as the high risk rare-coding pathogenic nsSNP, deviating protein functions. The 3D-modeling analysis of AN drugs' binding energies indicated lowest binding free energy (ΔG) and signi cant inhibition constant (K i ) with mutant models C30Y.Conclusions Mutant model (C30Y) exhibiting signi cant drug binding a nity and the commonest interaction observed at the acetylation site K59. Thus, based on these ndings, we concluded that the identi ed nsSNP may serve as potential targets for various studies, diagnosis and therapeutic interventions. Level of evidence No level of evidenceWhat Is Already Know On The Subject? Lombardi et al., 2019 and Ceccarrini et al in 2021 reported the role of con rmation of the involvement of the NNAT gene in the pathogenesis of AN. Further, its role in energy metabolic homeostasis has been clearly established through a vast spectrum of literature. What your study adds?Transcript level predictions of rare-coding high risk pathogenic human NNAT gene's SNPs by different in silico ML algorithms and their functional impact on protein stability. Characterizing the structural inference of rare-coding deleterious missense mutations and computing the molecular binding energies of most pathogenic 3D model of NNAT variant with therapeutic compounds of AN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa

et al. 2022

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“…To establish a diagnosis of an eating problem, the should be physically checked and his or her mental state evaluated, all of which should be backed by a complete medical history, family history, and social background. All symptoms must be listed chronologically (Bryant et al, 2022;Ceccarini et al, 2022;LaMarre et al, 2022).…”

Section: Differential Diagnosismentioning

confidence: 99%

Eating Disorders: Causes, Symptoms, Diagnosis and Management

agarwal¹

2022

Preprint

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Eating disorders, which are well-known in society as a significant mental health issue, have beencategorized as feeding and eating disorders in DSM-5 and the 11th version of ICD. In addition toanorexia and bulimia nervosa, the new categorization incorporates binge eating disorder as well asavoidant-restrictive food intake disorder (ARFID). They are regarded significant conditions withsubstantial morbidity and mortality risks that disproportionately impact the young group. Accordingto current studies, there is an upsurge in both age and sex demographics. A variety of genetic andphysiological variables, an insecure personality type, impulsive tendencies, dysfunctional emotionmanagement, and society's ideal of slimness have all been linked to the development of thesediseases. Throughout the psychotherapeutic therapies for all forms of eating disorders, a dualapproach with a focus on the symptom and the underlying issues is required. It is critical to evaluatecomorbid psychiatric and medical symptoms. With reference to the increased categories, furtherresearch and novel treatment approaches are required.

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“…The pathogenesis of EDs ensues from a pattern of genetic, psychosocial, biological, and environmental risk factors [ 9 , 10 ], and its complexity is often increased by the shift from one to another eating disorder diagnosis [ 6 , 11 ] (typically within the first 5 years of illness), suggesting an overlapping pathogenesis of this type of disorder [ 12 ]. In particular, it has been demonstrated that EDs share common neurobiological abnormalities, such as dysregulation of the serotonergic system [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

SLC6A4 DNA Methylation Levels and Serum Kynurenine/Tryptophan Ratio in Eating Disorders: A Possible Link with Psychopathological Traits?

et al. 2023

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Background: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients. Among these, 45 patients were affected by restricting anorexia nervosa (AN0), 21 by purging AN (AN1), 21 by bulimia (BN), 31 by binge eating disorders (BED), 23 by unspecified feeding or eating disorders (UFED), and finally 14 by other specified eating disorders (OSFED) were compared to 34 healthy controls (CTRs). Results: Kyn level was higher in BED, UFED, and OSFED compared to CTRs (p ≤ 0.001). On the other hand, AN0, AN1, and BN patients showed significatively lower Kyn levels compared to the other three ED groups but were closed to CTRs. Trp was significantly higher in AN0, AN1, and BN in comparison to other ED groups. Moreover, AN1 and BN showed more relevant Trp levels than CTRs (p <0.001). BED patients showed a lower Trp as compared with CTRs (p ≤ 0.001). In addition, Kyn/Trp ratio was lower in the AN1 subtype but higher in BED, UFED, and OSFED patients than in CTRs (p ≤ 0.001). SCL6A4 DNA methylation level at CpG5 was lower in AN0 compared to BED (p = 0.021), and the CpG6 methylation was also significantly lower in AN0 in comparison to CTRs (p = 0.025). The mean methylation levels of the six CpGs analyzed were lower only in the AN0 subgroup compared to CTRs (p = 0.008). Relevant psychological trait EDI-3 subscales were correlated with biochemical and epigenetic data. Conclusions: These findings underline the complexity of psychological and pathophysiological components of EDs.

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A next generation sequencing gene panel for use in the diagnosis of anorexia nervosa

Cited by 12 publications

References 70 publications

In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa

In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa

Eating Disorders: Causes, Symptoms, Diagnosis and Management

SLC6A4 DNA Methylation Levels and Serum Kynurenine/Tryptophan Ratio in Eating Disorders: A Possible Link with Psychopathological Traits?

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