Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement

Skakkebæk, Anne; Moore, P.J.; Pedersen, Anders Degn; Bojesen, Anders; Kristensen, Maria Krarup; Fedder, Jens; Hertz, Jens Michael; Østergaard, John R.; Wallentin, Mikkel; Gravholt, Claus Højbjerg

doi:10.1371/journal.pone.0206932

Cited by 28 publications

(25 citation statements)

References 51 publications

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“…Compared to all genes in the genome, genes on the X chromosome are enriched for expression in brain and embryonic development and also mental retardation, suggesting that chromosome-wide epigenetic dysregulation of the X chromosome may predispose individuals to neurodevelopmental disorders. Additional evidence for this premise can be seen in X chromosome aneuploidy disorders such as Turner, Klinefelter, and trisomy X syndromes, where differences in neuroanatomy and behavior have been identified [46][47][48][49][50][51]. Interestingly, both Klinefelter and trisomy X subjects are at a more than four-fold increased risk of having ASD [51].…”

Section: Discussionmentioning

confidence: 96%

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Mordaunt

Jianu

Laufer

et al. 2019

Preprint

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Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Results:We identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in postmortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain 3 development. Conclusions:At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sexbiased etiology of ASD, and provides novel insights for early diagnosis and therapy. Keywordsautism spectrum disorder, neurodevelopment, umbilical cord blood, prospective study, epigenome wide association study, epigenetics, epigenome, DNA methylation, whole genome bisulfite sequencing, x chromosome Background Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that affects 1 in 59 children in the United States [1]. ASD presents as persistent difficulties in social communication and interaction, restricted and repetitive behaviors and interests, as well as sensory sensitivities. Communication deficits can include delayed and monotonous speech, echolalia, poor verbal comprehension, difficulty understanding body language cues, and making eye contact, while behavioral deficits can include stereotyped movements, insistence on routine, fixated interests, and altered sensitivity to sensory input. ASD is currently diagnosed in childhood by one of several standardized scales that include interviews, behavioral observation, and clinical assessment, such as the gold standard Autism Diagnostic Observation Schedule (ADOS) [2,3]. Clinical management of ASD symptoms consists of both behavioral interventions and pharmacological treatments. Intensive behavioral interventions have been associated with better outcomes in children with ASD, especially for those diagnosed withi...

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Section: Discussionmentioning

confidence: 96%

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Mordaunt

Jianu

Laufer

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Compared to all genes in the genome, genes on the X chromosome are enriched for expression in brain and embryonic development and also mental retardation, suggesting that chromosome-wide epigenetic dysregulation of the X chromosome may predispose individuals to neurodevelopmental disorders. Additional evidence for this premise can be seen in X chromosome aneuploidy disorders such as Turner, Klinefelter, and trisomy X syndromes, where differences in neuroanatomy and behavior have been identified [105][106][107][108][109][110]. Interestingly, both Klinefelter and trisomy X subjects are at a more than fourfold increased risk of having ASD [110].…”

Section: Discussionmentioning

confidence: 96%

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

et al. 2020

View full text Add to dashboard Cite

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. Methods We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. Results We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. Conclusions At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.

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“…Patients with KS might have also exhibit impairments in executive functions related to attention, flexibility and planning as well as response inhibition 158 . The risks of developing psychiatric conditions, such as schizophrenia, bipolar disorders, depression, anxiety, autism and ADHD are increased in patients with KS 159‐163 …”

Section: Clinical Pictures Diagnostic Steps and Therapymentioning

confidence: 99%

“…In addition, the effects of anti-osteoporotic drugs on BMD and fracture risk in KS have not been studied. [159][160][161][162][163] Psychosexual development is often delayed and sexual problems might be more frequent in KS. 164 Most patients identify as male, but gender incongruence in KS has been reported in some studies.…”

Section: Evidencementioning

confidence: 99%

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

et al. 2020

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Background Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. Objective To create the first European Academy of Andrology (EAA) guidelines on KS. Methods An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone‐related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. Conclusion These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts.

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Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement

Cited by 28 publications

References 51 publications

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

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