Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype

Breen, Michael S.; Garg, Paras; Tang, Lara; Mendonca, Danielle; Levy, Tess; Barbosa, Mafalda; Arnett, Anne B.; Kurtz-Nelson, Evangeline; Agolini, Emanuele; Battaglia, Agatino; Chiocchetti, Andreas G.; Freitag, Christine M.; García-Alcón, Alicia; Grammatico, Paola; Hertz‐Picciotto, Irva; Ludena-Rodriguez, Yunin; Moreno, Carmen; Novelli, Antonio; Parellada, Mara; Pascolini, Giulia; Tassone, Flora; Grice, Dorothy E.; Marino, Daniele Di; Bernier, Raphael; Kolevzon, Alexander; Sharp, Andrew J.; Buxbaum, Joseph D.; Siper, Paige M.; Rubeis, Silvia De

doi:10.1016/j.ajhg.2020.07.003

Cited by 32 publications

(38 citation statements)

References 35 publications

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Section: Discussioncontrasting

confidence: 92%

“…Interestingly, pain insensitivity was common in this cohort, despite low levels of hyporeactivity in auditory and visual modalities. Our findings did not replicate previous literature describing a more severe phenotype associated with the recurrent p.Tyr719* variant [3]; however, results are consistent with Breen et al 2020 [43], which included some participants in this cohort and showed no phenotypic differences based on methylation group. ASD diagnosis and severity did not impact sensory symptoms identified by the SAND, SSP, or ADOS-2, indicating that the sensory phenotype in ADNP is generalizable across the syndrome, rather than driven by a subset with ASD.…”

Section: Discussioncontrasting

confidence: 92%

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Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis

Siper

Layton

Levy

et al. 2021

Genes

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Background: Activity dependent neuroprotective protein (ADNP) syndrome is one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability, however, the phenotypes remain poorly described. Here we examine the sensory reactivity phenotype in children and adolescents with ADNP syndrome. Methods: Twenty-two individuals with ADNP syndrome received comprehensive clinical evaluations including standardized observations, caregiver interviews, and questionnaires to assess sensory reactivity symptoms. Relationships between sensory symptoms and age, sex, ASD, IQ, and adaptive behavior were examined. Genotype-phenotype correlations with the recurrent p.Tyr719* variant were also explored. Results: Sensory reactivity symptoms were observed and reported in all participants. A syndrome-specific phenotype was identified, characterized by high levels of sensory seeking across tactile, auditory, and visual domains. Tactile hyporeactivity, characterized by pain insensitivity, was reported in the majority of participants. Sensory symptoms were identified across individuals regardless of age, sex, IQ, adaptive ability, genetic variant, and most importantly, ASD status. No significant differences were identified between participants with and without the recurrent p.Tyr719* variant on any sensory measure. Conclusions: Sensory reactivity symptoms are a common clinical feature of ADNP syndrome. Quantifying sensory reactivity using existing standardized measures will enhance understanding of sensory reactivity in individuals with ADNP syndrome and will aid in clinical care. The sensory domain may also represent a promising target for treatment in clinical trials.

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Section: Discussioncontrasting

confidence: 92%

Section: Discussioncontrasting

confidence: 92%

Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis

Siper

Layton

Levy

et al. 2021

Genes

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“…It is frequently associated with developmental delays, intellectual delays, motor planning delays, delayed or absent speech, and autism features of varying degrees [49]. A potential role in self-injurious behavior has also been suggested [50]. Multiple body systems may be affected, including the brain (e.g., developmental delay, intellectual disability), heart (e.g., atrial septal defect, patent ductus arteriosus), immune system (e.g., frequent infections), gastrointestinal system (e.g., gastroesophageal reflux, constipation), endocrine system (e.g., early puberty, thyroid hormone problems), and musculoskeletal system (e.g., joint hypermobility, scoliosis) [49].…”

Section: Discussionmentioning

confidence: 99%

Additional Evidence for Neuropsychiatric Manifestations in Mosaic Trisomy 20: A Case Report and Brief Review

et al. 2021

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Mosaic trisomy 20 is a genetic condition in which three chromosomes 20 are found in some cells. Its clinical phenotype seems to be highly variable, with most features not reported across all individuals and not considered pathognomonic of the condition. Limited and recent evidence indicates that neuropsychiatric manifestations may be more present in the context of trisomy 20 than was once thought. Here, we present a case of a 14-year-old female adolescent of White/Caucasian ethnicity with mosaic trisomy 20, who was admitted twice to an inpatient Child and Adolescent Neuropsychiatry Unit for persisting self-injury and suicidal ideation. A severe and complex neuropsychiatric presentation emerged at the cognitive, emotional, and behavioral levels, including mild neurodevelopmental issues, isolation, socio-relational difficulties, depressed mood, temper outbursts, irritability, low self-esteem, lack of interest, social anxiety, panic attacks, self-cutting, and low-average-range and heterogeneous intelligence quotient profile. Particularly, the patient was considered at high risk of causing harm, mainly to self, and appeared to be only partially responsive to medication, even when polypharmacy was attempted to improve clinical response. Except for school bullying, no other severe environmental risk factors were present in the patient’s history. The patient received a diagnosis of disruptive mood dysregulation disorder.

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“…Other examples of genes with multiple signatures are SRCAP (Floating Harbor syndrome and DEHMBA) (Rots et al, 2021), KMT2D (Kabuki syndrome and CHARGE-like phenotype) (Cuvertino et al, 2020) and KAT6B (GTPTS and SBBYSS) (Aref-Eshghi et al, 2020). Interestingly, truncating variants in different parts of the ADNP gene do result in different signatures, however these patients do show only minimal differences in clinical presentation (Bend et al, 2019;Breen et al, 2020).…”

Section: Dnam Arrays and Genomic Imprinting Disordersmentioning

confidence: 99%

Further Introduction of DNA Methylation (DNAm) Arrays in Regular Diagnostics

et al. 2022

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Methylation tests have been used for decades in regular DNA diagnostics focusing primarily on Imprinting disorders or specific loci annotated to specific disease associated gene promotors. With the introduction of DNA methylation (DNAm) arrays such as the Illumina Infinium HumanMethylation450 Beadchip array or the Illumina Infinium Methylation EPIC Beadchip array (850 k), it has become feasible to study the epigenome in a timely and cost-effective way. This has led to new insights regarding the complexity of well-studied imprinting disorders such as the Beckwith Wiedemann syndrome, but it has also led to the introduction of tests such as EpiSign, implemented as a diagnostic test in which a single array experiment can be compared to databases with known episignatures of multiple genetic disorders, especially neurodevelopmental disorders. The successful use of such DNAm tests is rapidly expanding. More and more disorders are found to be associated with discrete episignatures which enables fast and definite diagnoses, as we have shown. The first examples of environmentally induced clinical disorders characterized by discrete aberrant DNAm are discussed underlining the broad application of DNAm testing in regular diagnostics. Here we discuss exemplary findings in our laboratory covering this broad range of applications and we discuss further use of DNAm tests in the near future.

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Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype

Cited by 32 publications

References 35 publications

Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis

Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis

Additional Evidence for Neuropsychiatric Manifestations in Mosaic Trisomy 20: A Case Report and Brief Review

Further Introduction of DNA Methylation (DNAm) Arrays in Regular Diagnostics

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