RESUMEN
Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1 retrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 10-4 per locus per generation. Recurrent inversions exhibit a sex-chromosomal bias and co-localize with genomic disorder critical regions. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes specific haplotypes to disease-causing CNVs.
Asunto(s)
Inversión Cromosómica , Duplicaciones Segmentarias en el Genoma , Inversión Cromosómica/genética , Variaciones en el Número de Copia de ADN/genética , Genoma Humano , Genómica , HumanosRESUMEN
Chromosome 16p11.2 reciprocal genomic disorder, resulting from recurrent copy-number variants (CNVs), involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia, but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, and white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue-, cell-type-, and dosage-specific, although more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2,163 differentially expressed genes), and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated, loss-of-function constraint, and fragile X messenger ribonucleoprotein target gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, and single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Changes both in neuronal ratios and in gene expression in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption that might contribute to changes in neurodevelopmental and cognitive function in 16p11.2 carriers. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes and that this disruption has relative impacts that are context specific.
Asunto(s)
Trastorno del Espectro Autista , Trastornos de los Cromosomas , Discapacidad Intelectual , Animales , Trastorno del Espectro Autista/genética , Calbindina 2/genética , Corteza Cerebral , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 16/genética , Variaciones en el Número de Copia de ADN , Genómica , Humanos , Discapacidad Intelectual/genética , Ratones , Neuronas , ARNRESUMEN
Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.
Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos Par 3 , Variaciones en el Número de Copia de ADN , Fenotipo , Humanos , Femenino , Masculino , Cromosomas Humanos Par 3/genética , Duplicación Cromosómica/genética , Niño , Variaciones en el Número de Copia de ADN/genética , Preescolar , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Adolescente , Estudios de Cohortes , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Adulto , LactanteRESUMEN
3q29 deletion syndrome (3q29del) is a rare genomic disorder caused by a 1.6 Mb deletion (hg19, chr3:195725000-197350000). 3q29del is associated with neurodevelopmental and psychiatric phenotypes, including an astonishing >40-fold increased risk for schizophrenia, but medical phenotypes are less well-described. We used the online 3q29 registry of 206 individuals (3q29deletion.org) to recruit 57 individuals with 3q29del (56.14% male) and requested information about musculoskeletal phenotypes with a custom questionnaire. 85.96% of participants with 3q29del reported at least one musculoskeletal phenotype. Congenital anomalies were most common (70.18%), with pes planus (40.35%), pectus excavatum (22.81%), and pectus carinatum (5.26%) significantly elevated relative to the pediatric general population. 49.12% of participants reported fatigue after 30 min or less of activity. Bone fractures (8.77%) were significantly elevated relative to the pediatric general population. Participants commonly report receiving medical care for musculoskeletal complaints (71.93%), indicating that these phenotypes impact quality of life for individuals with 3q29del. This is the most comprehensive description of musculoskeletal phenotypes in 3q29del to date, suggests ideas for clinical evaluation, and expands our understanding of the phenotypic spectrum of this syndrome.
Asunto(s)
Discapacidades del Desarrollo , Discapacidad Intelectual , Humanos , Niño , Masculino , Femenino , Discapacidades del Desarrollo/genética , Deleción Cromosómica , Calidad de Vida , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Fenotipo , SíndromeRESUMEN
Large structural chromosomal deletions and duplications, referred to as copy number variants (CNVs), play a role in the pathogenesis of neurodevelopmental disorders (NDDs) through effects on gene dosage. This review focuses on our current understanding of genomic disorders that arise from large structural chromosome rearrangements in patients with NDDs, as well as difficulties in overlap of clinical presentation and molecular diagnosis. We discuss the implications of epigenetics, specifically DNA methylation (DNAm), in NDDs and genomic disorders, and consider the implications and clinical impact of copy number and genomic DNAm testing in patients with suspected genetic NDDs. We summarize evidence of global methylation episignatures in CNV-associated disorders that can be used in the diagnostic pathway and may provide insights into the molecular pathogenesis of genomic disorders. Finally, we discuss the potential for combining CNV and DNAm assessment into a single diagnostic assay.
Asunto(s)
Variaciones en el Número de Copia de ADN , Trastornos del Neurodesarrollo , Metilación de ADN , Epigénesis Genética , Epigenómica , Humanos , Trastornos del Neurodesarrollo/genéticaRESUMEN
Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.
Asunto(s)
Inversión Cromosómica , Síndrome de DiGeorge/genética , Predisposición Genética a la Enfermedad , Meiosis , Polimorfismo de Nucleótido Simple , Deleción Cromosómica , Variaciones en el Número de Copia de ADN , Síndrome de DiGeorge/patología , Recombinación Homóloga , Humanos , Hibridación Fluorescente in Situ/métodosRESUMEN
3q29 duplication syndrome (3q29dup) is a rare genomic disorder caused by a 1.6 Mb duplication (GRCh38 chr3:195,998,000-197,623,000). Case reports indicate the 3q29dup is likely to be pathogenic, but the full range of manifestations is not well understood. We used the 3q29 registry (https://3q29.com) to ascertain 31 individuals with 3q29dup, the largest cohort ever surveyed in a systematic way. For comparison, we ascertained 117 individuals with the reciprocal 3q29 deletion and 64 typically developing controls. We used a custom medical and demographic questionnaire to assess physical and developmental phenotypes, and two standardized instruments, the Social Responsiveness Scale and Child Behavior Checklist/Adult Behavior Checklist, to assess social disability. Participants with 3q29dup report a high rate of problems in the first year of life (80.6%), including feeding problems (55%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%). In early childhood, learning problems (71.0%) and seizures (25.8%) are common. Additionally, the rate of self-reported autism spectrum disorder diagnoses (39%) is substantially elevated compared to the general population, suggesting that the 3q29 duplication may be an autism susceptibility locus. This is the most comprehensive description of 3q29dup to date. Our findings can be used to develop evidence-based strategies for early intervention and management of 3q29dup.
Asunto(s)
Duplicación Cromosómica/genética , Cromosomas Humanos Par 3/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Adolescente , Adulto , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Niño , Preescolar , Deleción Cromosómica , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Sistema de Registros , Adulto JovenRESUMEN
22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.
Asunto(s)
Síndrome de DiGeorge/etiología , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 22 , Comorbilidad , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/epidemiología , Femenino , Enfermedades Gastrointestinales/etiología , Cardiopatías Congénitas/etiología , Humanos , Estudios Longitudinales , Masculino , Mortalidad , Philadelphia/epidemiología , Transición a la Atención de AdultosRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to summarize the role of genomic disorders in various psychiatric conditions and to highlight important recent advances in the field that are of potential clinical relevance. RECENT FINDINGS: Genomic disorders are caused by large rare recurrent deletions and duplications at certain chromosomal "hotspots" (e.g., 22q11.2, 16p11.2, 15q11-q13, 1q21.1, 15q13.3) across the genome. Most overlap multiple genes, affect development, and are associated with variable cognitive and other neuropsychiatric expression. Although individually rare, genomic disorders collectively account for a significant minority of intellectual disability, autism spectrum disorder, and schizophrenia. Genome-wide chromosomal microarray analysis is capable of detecting all genomic disorders in a single test, offering the first opportunity for routine clinical genetic testing in psychiatric practice.
Asunto(s)
Trastorno del Espectro Autista/genética , Enfermedades Genéticas Congénitas/psicología , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Esquizofrenia/genética , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Enfermedades Genéticas Congénitas/genética , Estudio de Asociación del Genoma Completo , Genómica , Humanos , PsiquiatríaRESUMEN
22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. Survival to reproductive age and beyond is now the norm. Several manifestations of this syndrome, such as congenital cardiac disease and neuropsychiatric disorders, may increase risk for adverse pregnancy outcomes in the general population. However, there are limited data on reproductive health in 22q11.2DS. We performed a retrospective chart review for 158 adults with 22q11.2DS (75 male, 83 female; mean age 34.3 years) and extracted key variables relevant to pregnancy and reproductive health. We present four illustrative cases as brief vignettes. There were 25 adults (21 > age 35 years; 21 female) with a history of one or more pregnancies. Outcomes for women with 22q11.2DS, compared with expectations for the general population, showed a significantly elevated prevalence of small for gestational age liveborn offspring (p < 0.001), associated mainly with infants with 22q11.2DS. Stillbirths also showed elevated prevalence (p < 0.05). Not all observed adverse events appeared to be attributable to transmission of the 22q11.2 deletion. Recurring issues relevant to reproductive health in 22q11.2DS included the potential impact of maternal morbidities, inadequate social support, unsafe sexual practices, and delayed diagnosis of 22q11.2DS and/or lack of genetic counseling. These preliminary results emphasize the importance of early diagnosis and long term follow-up that could help facilitate genetic counseling for men and women with 22q11.2DS. We propose initial recommendations for pre-conception management, educational strategies, prenatal planning, and preparation for possible high-risk pregnancy and/or delivery.
Asunto(s)
Síndrome de DiGeorge/epidemiología , Asesoramiento Genético/estadística & datos numéricos , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo/epidemiología , Salud Reproductiva/estadística & datos numéricos , Adulto , Comorbilidad , Síndrome de DiGeorge/genética , Femenino , Cardiopatías Congénitas/epidemiología , Humanos , Masculino , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/prevención & control , Resultado del Embarazo/genética , Atención Prenatal/estadística & datos numéricos , Estudios Retrospectivos , Adulto JovenRESUMEN
Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity.
Asunto(s)
Puntos de Rotura del Cromosoma , Conversión Génica , Genes de Neurofibromatosis 1 , Recombinación Homóloga , Meiosis , Mitosis , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Cromosomas Humanos Par 17 , Reparación de la Incompatibilidad de ADN , Mutación de Línea Germinal , Humanos , Mosaicismo , Análisis de Secuencia de ADN , Eliminación de SecuenciaRESUMEN
New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression.
Asunto(s)
Duplicación Cromosómica/genética , Segregación Cromosómica/genética , Cromosomas Humanos Par 2/genética , Pruebas Neuropsicológicas , Adulto , Variaciones en el Número de Copia de ADN/genética , Familia , Femenino , Asesoramiento Genético , Pruebas Genéticas , Genotipo , Humanos , Masculino , Linaje , FenotipoRESUMEN
Background: Genomic disorders caused by copy number variations (CNVs) are prevalent in patients with kidney disease; however, their contribution to chronic kidney failure (KF) of undetermined aetiology (uKF) is unclear. We screened patients with uKF aged 50 years or younger to establish the prevalence of causative CNVs. Methods: We enrolled patients with an onset of KF ≤50 years from suspected undetermined aetiology for initial review of medical records to exclude patients with clear-cut clinical or histopathological kidney diagnoses or patients with already established genetic kidney diseases. Next, we performed single nucleotide polymorphism (SNP) array-based CNV screening. All the detected CNVs were systematically classified and evaluated as possible causes of the patient's kidney disease. Patients with CNVs not explaining the kidney phenotype were additionally screened for causal variants in 540 genes using whole-genome sequencing. Results: We enrolled 172 patients, of whom 123 underwent SNP-array. Pathogenic CNVs corresponding to known genomic disorders were identified in 12 patients (9.8%). The identified genomic disorders provided a causative kidney diagnosis in three patients, all of whom had reached KF by age 18 years. The remaining nine patients had CNVs with unclear kidney disease causality. Subsequently, whole-genome sequencing provided a causative genetic diagnosis in an additional four patients, including two diagnostic sequence variants unrelated to the detected CNVs. Conclusions: Genomic disorders were prevalent in this cohort with uKF, and causative CNVs were identified in 5 of 123 patients. Further studies combining the analysis of CNVs and sequence variants are needed to clarify the causal role of genomic disorders in kidney disease.
RESUMEN
BACKGROUND: Delineating base-resolution breakpoints of complex rearrangements is crucial for an accurate clinical understanding of pathogenic variants and for carrier screening within family networks or the broader population. However, despite advances in genetic testing using short-read sequencing (SRS), this task remains costly and challenging. METHODS: This study addresses the challenges of resolving missing disease-causing breakpoints in complex genomic disorders with suspected homozygous rearrangements by employing multiple long-read sequencing (LRS) strategies, including a novel and efficient strategy named nanopore-based rapid acquisition of neighboring genomic regions (NanoRanger). NanoRanger does not require large amounts of ultrahigh-molecular-weight DNA and stands out for its ease of use and rapid acquisition of large genomic regions of interest with deep coverage. FINDINGS: We describe a cohort of 16 familial cases, each harboring homozygous rearrangements that defied breakpoint determination by SRS and optical genome mapping (OGM). NanoRanger identified the breakpoints with single-base-pair resolution, enabling accurate determination of the carrier status of unaffected family members as well as the founder nature of these genomic lesions and their frequency in the local population. The resolved breakpoints revealed that repetitive DNA, gene regulatory elements, and transcription activity contribute to genome instability in these novel recessive rearrangements. CONCLUSIONS: Our data suggest that NanoRanger greatly improves the success rate of resolving base-resolution breakpoints of complex genomic disorders and expands access to LRS for the benefit of patients with Mendelian disorders. FUNDING: M.L. is supported by KAUST Baseline Award no. BAS/1/1080-01-01 and KAUST Research Translation Fund Award no. REI/1/4742-01.
RESUMEN
22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.
Asunto(s)
Síndrome de DiGeorge , Humanos , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/complicaciones , Fenotipo , Análisis por MicromatricesRESUMEN
BACKGROUND: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail. METHODS: Thirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators. RESULTS: Subjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD. LIMITATIONS: There were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects. CONCLUSIONS: 3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.
Asunto(s)
Trastorno del Espectro Autista , Masculino , Femenino , Humanos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Síndrome , Habilidades Sociales , Encuestas y Cuestionarios , FenotipoRESUMEN
Cytotoxic chemotherapeutics are common treatment methods of many cancers, and patients are often dosed at maximum tolerated dose (MTD), which is trying to eliminate cancer cells as much as possible. However, highly doses chemotherapy may induce unexpected gene mutations or DNA recombinations, which in turn result in unpredictable outcomes and drug resistance. In this study, we focus on the occurrence of DNA recombinations, and present a mathematical model for the influence of genomic disorder due to chemotherapy, and investigate how it may lead to drug resistance. We show that there is an optimal dose so that the tumor cells number is minimum at the steady state, which suggests the existence of an optimal dose of chemotherapy below the MTD. Model simulations show that when the dose is either low or high, the tumor cancer cells number may maintain a higher level steady state, or even sustained oscillations when the dose is too high, which are clinically inappropriate. Our results provide a theoretical study on the dose control of chemotherapy in cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Cromosomas/genética , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Recombinación Genética , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis , Diferenciación Celular , Proliferación Celular , Senescencia Celular , Humanos , Dosis Máxima Tolerada , Mitosis , Modelos Teóricos , Recurrencia Local de Neoplasia , Células Madre Neoplásicas/citología , OscilometríaRESUMEN
Background: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and psychiatric phenotypes, including increased risk for autism spectrum disorder (ASD) and a 20 to 40-fold increased risk for schizophrenia. However, the phenotypic spectrum of the deletion, particularly with respect to ASD, remains poorly described. Methods: We ascertained individuals with 3q29 deletion syndrome (3q29Del, "cases," n = 93, 58.1% male) and typically developing controls (n = 64, 51.6% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 93 cases. Subsets of participants were evaluated with the Social Responsiveness Scale (SRS, n = 48 cases, 56 controls), Social Communication Questionnaire (n = 33 cases, 46 controls), Autism Spectrum Screening Questionnaire (n = 24 cases, 35 controls), and Achenbach Behavior Checklists (n = 48 cases, 57 controls). Results: 3q29Del cases report a higher prevalence of autism diagnoses versus the general population (29.0% vs. 1.47%, p < 2.2E- 16). Notably, 3q29 deletion confers a greater influence on risk for ASD in females (OR = 41.8, p = 4.78E- 05) than in males (OR = 24.6, p = 6.06E- 09); this is aligned with the reduced male:female bias from 4:1 in the general population to 2:1 in our study sample. Although 71% of cases do not report a diagnosis of ASD, there is evidence of significant social disability (3q29Del SRS T-score = 71.8, control SRS T-score = 45.9, p = 2.16E- 13). Cases also report increased frequency of generalized anxiety disorder compared to controls (28.0% vs. 6.2%, p = 0.001), which is mirrored by elevated mean scores on the Achenbach diagnostic and statistical manual-oriented sub-scales (p < 0.001). Finally, cases show a distinct constellation of ASD features on the SRS as compared to idiopathic ASD, with substantially elevated Restricted Interests and Repetitive Behaviors, but only mild impairment in Social Motivation. Conclusions: Our sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the constellation of ASD features in this population is distinct from idiopathic ASD, with substantially less impaired social motivation. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the distinct ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.
Asunto(s)
Trastorno del Espectro Autista/psicología , Discapacidad Intelectual/psicología , Pruebas Neuropsicológicas , Sistema de Registros , Adolescente , Adulto , Trastorno del Espectro Autista/diagnóstico , Estudios de Casos y Controles , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 3 , Factores de Confusión Epidemiológicos , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/psicología , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Fenotipo , Estándares de Referencia , Autoinforme , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Copy number variation (CNV) disorders arise from the dosage imbalance of one or more gene(s), resulting from deletions, duplications or other genomic rearrangements that lead to the loss or gain of genetic material. Several disorders, characterized by multiple birth defects and neurodevelopmental abnormalities, have been associated with relatively large (>1 Mb) and often recurrent CNVs. CNVs have also been implicated in the etiology of neuropsychiatric disorders including autism and schizophrenia as well as other common complex diseases. Thus, CNVs have a significant impact on human health and disease. RECENT FINDINGS: The use of increasingly higher resolution, genomewide analysis has greatly enhanced the detection of genetic variation, including CNVs. Furthermore, the availability of comprehensive genetic variation data from large cohorts of healthy controls has the potential to greatly improve the identification of disease associated genetic variants in patient samples. SUMMARY: This review discusses the current knowledge about CNV disorders, including the mechanisms underlying their formation and phenotypic outcomes, and the advantages and limitations of current methods of detection and disease association.
RESUMEN
Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.