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PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. METHODS: We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.
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Data repositories, particularly those storing data on vulnerable populations, increasingly need to carefully consider not only what data is being collected, but how it will be used. As such, the Autism Intervention Research Network on Physical Health (AIR-P) has created the Infrastructure for Collaborative Research (ICR) to establish standards on data collection practices in Autism repositories. The ICR will strive to encourage inter-site collaboration, amplify autistic voices, and widen accessibility to data. The ICR is staged as a three-tiered framework consisting of (1) a request for proposals system, (2) a REDCap-based data repository, and (3) public data dashboards to display aggregate de-identified data. Coupled with a review process including autistic and non-autistic researchers, this framework aims to propel the implementation of equitable autism research, enhance standardization within and between studies, and boost transparency and dissemination of findings. In addition, the inclusion of a contact registry that study participants can opt into creates the base for a robust participant pool. As such, researchers can leverage the platform to identify, reach, and distribute electronic materials to a greater proportion of potential participants who likely fall within their eligibility criteria. By incorporating practices that promote effective communication between researchers and participants, the ICR can facilitate research that is both considerate of and a benefit to autistic people.
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Trastorno Autístico , Humanos , Conducta Cooperativa , Investigación Biomédica/métodos , Investigación Biomédica/normas , Recolección de Datos/métodosRESUMEN
OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. RESULTS: One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.
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Trastorno del Espectro Autista , Epilepsia , Mutación de Línea Germinal , Fosfohidrolasa PTEN , Humanos , Masculino , Femenino , Adolescente , Niño , Preescolar , Adulto Joven , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Epilepsia/genética , Fosfohidrolasa PTEN/genética , Adulto , Síndrome de Hamartoma Múltiple/genéticaRESUMEN
INTRODUCTION: Autistic individuals, now representing one in 36 individuals in the U.S., experience disproportionate physical health challenges relative to non-autistic individuals. The Health Resources and Services Administration's (HRSA) Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multi-center Research Network that aims to increase the health, well-being, and quality of life of autistic individuals. The current paper builds on the initial AIR-P Research Agenda (proposed in Year 1) and provides an updated vision for the Network. METHODS: Updates to the Research Agenda were made via the administration of a Qualtrics survey, and disseminated widely to all AIR-P entities, including the Research Node Leaders, Steering Committee, Autistic Researcher Review Board, and collaborating academic and non-academic entities. Network members were tasked with evaluating the Year 1 Research Agenda and proposing additional priorities. RESULTS: Within each Research Node, all Year 1 priorities were endorsed as continued priorities for research on autism and physical health. Specific topics, including co-occurring conditions and self-determination, advocacy, and decision-making, were particularly endorsed. Opportunities for exploratory studies and intervention research were identified across Research Nodes. Qualitative responses providing feedback on additional research priorities were collected. CONCLUSION: The updated AIR-P Research Agenda represents an important step toward enacting large-scale health promotion efforts for autistic individuals across the lifespan. This updated agenda builds on efforts to catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health promotion.
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PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
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Anomalías Múltiples , Discapacidad Intelectual , Micrognatismo , Trastornos del Neurodesarrollo , Humanos , Anomalías Múltiples/genética , Cara , Micrognatismo/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Facies , Fenotipo , Proteínas de Unión al ADN/genética , Factores de Transcripción/genéticaRESUMEN
Equitable and just genetic research and clinical translation require an examination of the ethical questions pertaining to vulnerable and marginalized communities. Autism research and advocate communities have expressed concerns over current practices of genetics research, urging the field to shift towards paradigms and practices that ensure benefits and avoid harm to research participants and the wider autistic community. Building upon a framework of bioethical principles, we provide the background for the concerns and present recommendations for ethically sustainable and justice-oriented genetic and genomic autism research. With the primary goal of enhancing the health, well-being, and autonomy of autistic persons, we make recommendations to guide priority setting, responsible research conduct, and informed consent practices. Further, we discuss the ethical challenges particularly pertaining to research involving highly vulnerable individuals and groups, such as those with impaired cognitive or communication ability. Finally, we consider the clinical translation of autism genetics studies, including the use of genetic testing. These guidelines, developed by an interdisciplinary working group comprising autistic and non-autistic individuals, will aid in leveraging the potential of genetics research to enhance the quality of life of autistic individuals and are widely applicable across stigmatized traits and vulnerable communities.
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Trastorno Autístico , Humanos , Trastorno Autístico/genética , Calidad de Vida , Consentimiento Informado , Pruebas Genéticas , GenómicaRESUMEN
Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Adulto , Niño , Femenino , Humanos , Lactante , Masculino , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/genética , Fenotipo , Proteína Fosfatasa 2C/genética , Estudios Retrospectivos , Vómitos , Preescolar , Adolescente , Adulto Joven , Persona de Mediana EdadRESUMEN
BACKGROUND: Unbalanced translocations can cause developmental delay (DD), intellectual disability (ID), growth problems, dysmorphic features, and congenital anomalies. They may arise de novo or may be inherited from a parent carrying a balanced rearrangement. It is estimated that 1/500 people is a balanced translocation carrier. The outcomes of different chromosomal rearrangements have the potential to reveal the functional consequences of partial trisomy or partial monosomy and can help guide genetic counseling for balanced carriers, and other young patients diagnosed with similar imbalances. METHODS: We performed clinical phenotyping and cytogenetic analyses of two siblings with a history of developmental delay (DD), intellectual disability (ID) and dysmorphic features. RESULTS: The proband, a 38-year-old female, has a history of short stature, dysmorphic features and aortic coarctation. She underwent chromosomal microarray analysis, which identified partial monosomy of 4q and partial trisomy of 10p. Her brother, a 37-year-old male, has a history of more severe DD, behavioral problems, dysmorphic features, and congenital anomalies. Subsequently, karyotype confirmed two different unbalanced translocations in the siblings: 46,XX,der(4)t(4;10)(q33;p15.1) and 46,XY,der(10)t(4;10)(q33;p15.1), respectively. These chromosomal rearrangements represent two possible outcomes from a parent who is a carrier for a balanced translocation 46,XX,t(4;10)(q33;p15.1). CONCLUSION: To our knowledge, this 4q and 10p translocation has not been described in literature. In this report we compare clinical features due to the composite effects of partial monosomy 4q with partial trisomy 10p and partial trisomy 4q with partial monosomy 10p. These findings speak to the relevance of old and new genomic testing, the viability of these segregation outcomes, and need for genetic counseling.
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Trastornos de los Cromosomas , Discapacidad Intelectual , Humanos , Masculino , Femenino , Adulto , Deleción Cromosómica , Trisomía/genética , Discapacidad Intelectual/genética , Trastornos de los Cromosomas/genética , Translocación Genética , Aberraciones CromosómicasRESUMEN
BACKGROUND: Individuals with PTEN hamartoma tumor syndrome (PHTS) demonstrate a distinct neurobehavioral profile suggesting primary disruption of frontal lobe symptoms, with more severe cognitive deficits in those with associated autism spectrum disorder (ASD) that extend to other areas of neurobehavioral function as well (e.g., adaptive behavior, sensory deficits). The current study sought to characterize longitudinal neurobehavioral profiles in individuals with PHTS who completed serial assessments (2-3 evaluations) over a 2-year time period. METHODS: Comprehensive neurobehavioral evaluations were conducted on 92 participants (age range 6-21) with PHTS and/or ASD. Spaghetti plots and linear mixed effects models were used to visualize the individual patient profiles and group trends and examine the group differences in cognitive/behavioral test scores over time. Practice-adjusted reliable change indices (RCIs) and standardized regression-based change scores (SRBs) were calculated for those measures in the battery with adequate sample sizes and test-retest reliabilities for future use in assessing neurobehavioral change in children and young adults with PHTS. RESULTS: Wide individual differences were observed at baseline across all measures. Encouragingly, baseline differences between patient groups persisted at the same magnitude over a 2-year time period with no differences in longitudinal neurobehavioral profiles within any one group. Test-retest reliabilities were generally high, ranging from 0.62 to 0.97, and group mean change from baseline to 12 months was small (range - 3.8 to 3.7). A Microsoft Excel calculator was created that clinicians and researchers can use to automatically calculate RCI and SRB thresholds at both 80% and 90% confidence intervals using test scores from a given child or young adult with PHTS. CONCLUSIONS: Our results suggest that the neurobehavioral phenotypes observed in individuals with PHTS remain relatively stable over time, even in those with ASD. The RCIs and SRBs provided can be used in future research to examine patient outcomes at the individual level as well as to detect negative deviations from the expected trajectory that can be used to inform intervention strategies.
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Trastorno del Espectro Autista , Síndrome de Hamartoma Múltiple , Humanos , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Síndrome de Hamartoma Múltiple/diagnóstico , Pruebas Neuropsicológicas , Fenotipo , Fosfohidrolasa PTEN/genética , Niño , Adolescente , Adulto JovenRESUMEN
BACKGROUND: Dermatologic phenotypes in PTEN hamartoma tumor syndrome (PHTS) are heterogeneous and poorly documented. OBJECTIVE: To characterize dermatologic findings among PHTS and conduct an analysis of genotype-dermatologic phenotype associations. METHODS: Mucocutaneous findings were reviewed in a multicenter cohort study of PHTS. Genotype-dermatologic phenotype associations were tested using multivariable regression. RESULTS: A total of 201 patients were included. Children were significantly less likely than adults to have oral papillomas, vascular malformations, benign follicular neoplasms, and acral keratoses. There were no cases of skin cancer among children. Basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma developed in 5%, 2%, and 1% of White adults, respectively. After adjusting for age, missense mutations were associated with 60% lower odds of developing cutaneous papillomatous papules (odds ratio: 0.4; 95% confidence interval [0.2, 0.7]), oral papillomas (0.4; 95% confidence interval [0.2, 0.9]), and vascular malformations (0.4; 95% confidence interval [0.2, 0.8]). LIMITATIONS: Partly retrospective data. CONCLUSION: Children are less likely than adults to have certain dermatologic findings, likely due to age-related penetrance. The risk of pediatric melanoma and the lifetime risk of nonmelanoma skin cancer in PHTS may not be elevated. Missense variants may be associated with the development of fewer dermatologic findings but future validation is required.
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Carcinoma de Células Escamosas , Síndrome de Hamartoma Múltiple , Melanoma , Papiloma , Neoplasias Cutáneas , Malformaciones Vasculares , Humanos , Síndrome de Hamartoma Múltiple/complicaciones , Síndrome de Hamartoma Múltiple/epidemiología , Síndrome de Hamartoma Múltiple/genética , Carcinoma de Células Escamosas/complicaciones , Estudios Retrospectivos , Estudios de Cohortes , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/complicaciones , Melanoma/complicaciones , Malformaciones Vasculares/complicaciones , Fosfohidrolasa PTEN/genéticaRESUMEN
Endometriosis is a common reproductive disease with a heterogeneous presentation. Classification attempts have thus far not offered insight into its cause or its symptoms. Endometriosis may result from the migration of shed endometrium to the peritoneal cavity. However, there are cases reported in girls without uteruses and men. While a non-retrograde menstruation origin of ectopic tissue is certain in these cases, we explored the use of DNA methylation age (DNAm age) to distinguish between retrograde and non-retrograde tissue origin in endometriosis. Using publicly available DNA methylation data and Horvath's pan-tissue epigenetic clock, we compared DNAm age and epigenetic age acceleration (EAA) of ectopic lesions to eutopic endometrium of diseased and control endometrium. We examined EAA in cancer metastasis and teratomas to control for migration and developmental origin. Disease status does not change DNAm age of eutopic endometrium, but the effect of ectopic status was profound: - 16.88 years (p = 4.82 × 10-7). There were no differences between EAA of primary/metastatic tumor paired samples, suggesting that the observed effect is not due to tissue migration or ectopic location. Immature or mature teratoma compartments decreased DNAm age by 9.44 and 7.40 years respectively, suggesting that developmental state correlates with DNAm age. Ectopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue, but distinct from eutopic tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions suggests a distinct developmental origin for a subset of lesions. This finding may assist in classifying endometriosis into distinct subtypes that may be clinically relevant.
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Epigenómica , HumanosRESUMEN
Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.
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Proteínas de Unión al Calcio , Enfermedades Mitocondriales , Proteínas de Unión al Calcio/genética , Homeostasis/genética , Humanos , Proteínas de la Membrana/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Sistema Nervioso/metabolismo , Saccharomyces cerevisiae/metabolismoRESUMEN
Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.
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Trastornos del Neurodesarrollo , Proteínas de Unión al GTP rac , Animales , Humanos , Ratones , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Neuronas/metabolismo , Fenotipo , Quinasas p21 Activadas/genética , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismoRESUMEN
OBJECTIVES: In the United States, autistic individuals experience disproportionate physical and mental health challenges relative to non-autistic individuals, including higher rates of co-occurring and chronic conditions and lower physical, social, and psychological health-related quality of life. The Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multicenter research network for scientific collaboration and infrastructure that aims to increase the life expectancy and quality of life for autistic individuals, with a focus on underserved or vulnerable populations. The current paper describes the development of the AIR-P Research Agenda. METHODS: Development of the research agenda involved an iterative and collaborative process between the AIR-P Advisory Board, Steering Committee, and Autistic Researcher Review Board. The methodology consisted of 3 phases: (1) ideation and design, (2) literature review and synthesis; and (3) network engagement. RESULTS: Six core research priorities related to the health of autistic individuals were identified: (1) primary care services and quality, (2) community-based lifestyle interventions, (3) health systems and services, (4) gender, sexuality, and reproductive health, (5) neurology, and (6) genetics. Specific topics within each of these priorities were identified. Four cross-cutting research priorities were also identified: (1) neurodiversity-oriented care, (2) facilitating developmental transitions, (3) methodologically rigorous intervention studies, and (4) addressing health disparities. CONCLUSIONS: The AIR-P Research Agenda represents an important step forward for enacting large-scale health-promotion efforts for autistic individuals across the lifespan. This agenda will catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health-promotion.
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Trastorno Autístico , Trastorno Autístico/psicología , Trastorno Autístico/terapia , Enfermedad Crónica , Humanos , Calidad de Vida , Estados UnidosRESUMEN
BACKGROUND: Prader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects. RESULTS: We report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant. CONCLUSIONS: This is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS.
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Síndrome de Prader-Willi , Niño , Femenino , Humanos , Cromosomas Humanos Par 15/genética , ADN , Metilación de ADN/genética , Impresión Genómica , Mucosa Bucal , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Proteínas Nucleares snRNP/genética , Polimorfismo de Nucleótido SimpleRESUMEN
This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with PTEN mutations and individuals with macrocephalic ASD. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; Mage = 8.93 years, SDage = 4.75), 23 with PTEN mutation without ASD (PTEN-no ASD; Mage = 8.94 years; SDage = 4.85) and 25 with ASD and macrocephaly but with no PTEN mutation (Macro-ASD; Mage = 11.99 years; SDage = 5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t = 4.12, p < 0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with PTEN mutations and with macrocephalic ASD.
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Trastorno del Espectro Autista , Mutación de Línea Germinal , Ansiedad/genética , Trastorno del Espectro Autista/genética , Niño , Preescolar , Células Germinativas , Humanos , Fosfohidrolasa PTEN/genética , PadresRESUMEN
Germline heterozygous PTEN mutations have been associated with high prevalence of autism spectrum disorder (ASD) and elevated rates and severity of broadly defined behavioral problems. However, limited progress has been made toward understanding whether PTEN mutation is associated with specific psychiatric co-morbidity profiles when compared to idiopathic ASD. The current study aimed to utilize a cross-measure approach to compare concurrent psychiatric characteristics across children and adolescents with PTEN mutation with (PTEN-ASD; n = 38) and without ASD (PTEN-No ASD; n = 23), and ASD with macrocephaly but no PTEN mutation (macro-ASD; n = 25) using the Child Behavior Checklist (CBCL) and the Aberrant Behavior Checklist (ABC). There were significant group effects for the CBCL Internalizing and Externalizing broad symptom score, the majority of specific CBCL syndrome scores, and all ABC subscale scores. Post-hoc comparisons revealed greater behavioral symptoms in the ASD groups (PTEN-ASD and macro-ASD) compared to the PTEN-no ASD group on nearly all subtest scores examined. There were no statistically significant differences between the PTEN-ASD and macro-ASD groups; however, there was a trend for the macro-ASD group showing higher levels of aggressive behaviors. Our findings provide evidence of specific behavior profiles across PTEN-No ASD, PTEN-ASD, and macro-ASD groups and highlight the importance of early identification of behavioral vulnerabilities in individuals with PTEN mutations in order to provide access to appropriate evidence-based interventions.
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This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage = 8.93 years, SDage = 4.75), 25 Macro-ASD (Mage = 11.99 years; SDage = 5.15), and 23 PTEN-No ASD (Mage = 8.94 years; SDage = 4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2 = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2 = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2 = 0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.