RESUMO
SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.
Assuntos
Região Branquial , Proteínas de Ligação à Região de Interação com a Matriz , Fenótipo , Fatores de Transcrição , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Animais , Humanos , Camundongos , Fatores de Transcrição/genética , Região Branquial/anormalidades , Região Branquial/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Feminino , Masculino , Camundongos Knockout , Síndrome , Mandíbula/anormalidades , Mandíbula/patologiaRESUMO
Alterations in SATB2 result in SATB2-associated syndrome (SAS; Glass syndrome, OMIM 612313), an autosomal dominant multisystemic disorder predominantly characterized by developmental delay, craniofacial anomalies, and growth retardation. The bone phenotype of SAS has been less explored until recently and includes a variety of skeletal deformities, increased risk of low bone mineral density (BMD) with a propensity to fractures, and other biochemical abnormalities that suggest elevated bone turnover. We present the results of ongoing surveillance of bone health from 32 individuals (47% females, 3-18 years) with molecularly-confirmed SAS evaluated at a multidisciplinary clinic. Five individuals (5/32, 16%) were documented to have BMD Z-scores by DXA scans of -2.0 SD or lower and 7 more (7/32, 22%) had Z-scores between -1 and - 2 SD at the lumbar spine or the total hip. Alkaline phosphatase levels were found to be elevated in 19 individuals (19/30, 63%) and determined to correspond to bone-specific alkaline phosphatase elevations when measured (11/11, 100%). C-telopeptide levels were found to be elevated when adjusted by age and gender in 6 individuals (6/14, 43%). Additionally, the two individuals who underwent bone cross-sectional geometry evaluation by peripheral quantitative computed tomography were documented to have low cortical bone density for age and sex despite concurrent DXA scans that did not have this level of decreased density. While we could not identify particular biochemical abnormalities that predicted low BMD, the frequent elevations in markers of bone formation and resorption further confirmed the increased bone turnover in SAS. Based on our results and other recently published studies, we propose surveillance guidelines for the skeletal phenotype of SAS.
Assuntos
Doenças Ósseas Metabólicas , Proteínas de Ligação à Região de Interação com a Matriz , Feminino , Humanos , Masculino , Densidade Óssea/genética , Fosfatase Alcalina , Estudos Prospectivos , Osso e Ossos/diagnóstico por imagem , Absorciometria de Fóton/métodos , Síndrome , Fatores de Transcrição/genética , Proteínas de Ligação à Região de Interação com a Matriz/genéticaRESUMO
SATB2-associated syndrome (SAS) is an autosomal dominant multisystemic disorder caused by alterations in the SATB2 gene. In addition to a predominant neurodevelopmental phenotype, individuals with SAS often present with feeding difficulties and growth retardation that persist past infancy. In this study, we present growth and measurement data from 211 individuals (53.6% male, 46.4% female) with SAS due to different molecular mechanisms. To delineate growth in this population, we constructed SAS-specific growth charts by sex from birth to 10 years of age. Smoothed SAS percentiles were superimposed with normative percentiles from WHO (birth to <24 months) and CDC (24 months to 10 years) growth charts. Individuals with SAS tend to display slower postnatal growth with 22.2% (32/144), 19.0% (26/137), and 21.6% having at least one weight, height, or weight-for-length /body mass index (BMI) measurement below -2 standard deviations, respectively. The SAS 50th centile BMI was consistently below the normative data 50th centile and negative mean Z-scores were seen across almost all age groups analyzed for both genders. Individuals with chromosomal abnormalities displayed significantly lower weight for age Z-score, height for age Z-scores, occipitofrontal head circumference for age Z-scores, and BMI for age Z-scores compared to either missense or null variants.
Assuntos
Gráficos de Crescimento , Proteínas de Ligação à Região de Interação com a Matriz , Índice de Massa Corporal , Peso Corporal , Feminino , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Síndrome , Fatores de Transcrição/genéticaRESUMO
SATB2-associated syndrome (SAS) is an autosomal dominant neurogenetic multisystemic disorder. We describe two individuals with global developmental delay and hypotonia who underwent an extensive evaluation to rule out an underlying mitochondrial disorder before their eventual diagnosis of SAS. Although the strict application of the clinical mitochondrial disease score only led to the designation of "possible" mitochondrial disorder for these two individuals, other documented abnormalities included nonspecific neuroimaging findings on magnetic resonance imaging and magnetic resonance spectroscopy, decreased complex I activity on muscle biopsy for patient 2, and variation in the size and relative proportion of types of muscle fibers in the muscle biopsies that were aligned with mitochondrial diseases. SAS should be in the differential diagnoses of mitochondrial disorders, and broad-spectrum diagnostic tests such as exome sequencing need to be considered early in the evaluation process of undiagnosed neurodevelopmental disorders.
RESUMO
The goal of this study was to investigate the medical, communication, activities of daily living (ADLs), and mental health concerns affecting adolescents and adults with SATB2-associated syndrome (SAS). A comprehensive questionnaire was administered to the caregivers of 49 individuals 12 years or older with SAS (mean age was 19.4 years, range 12-37 years). For all individuals, medical records, including laboratory results, were reviewed. Most individuals required some degree of assistance for ADLs and none of the adults were able to live independently. Health status was qualified as excellent or very good in 61% of individuals. The most common medical problems were dental anomalies, with a significantly higher frequency of hypotonia and gastroesophageal reflux in younger individuals. Medical and surgical interventions were often required. Sixty-nine percent (n = 33) of individuals spoke 10 or fewer words. Autism (41%), anxiety (37%), and attention deficit disorder (37%) were common with one third of individuals receiving medical treatments for these diagnoses. While medical and developmental problems in individuals with SAS were similar to those previously reported, many of these are persistent into adolescence and adulthood. This study provides better guidance for the challenges facing adults with SAS and their families.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fenótipo , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Sistema de Registros , Síndrome , Adulto JovemRESUMO
SATB2-associated syndrome (SAS) is a multisystemic disorder characterized by developmental delay often with concurrent autistic tendencies. This study aimed to characterize cellular metabolic pathways and energy metabolism from cells derived from individuals with SAS. The cellular production of NADH (nicotinamide adenine dinucleotide, reduced form) as determined by the Phenotype Mammalian MicroArrays was measured in lymphoblastoid cell lines derived from 11 subjects with a molecularly confirmed diagnosis of SAS and compared to a control population of 50 age-matched typically developing individuals. All patients were evaluated clinically by a multidisciplinary team. Eleven individuals (five in a screening cohort and six in the validation cohort, mean age 6.1 years) were recruited to the study. All individuals had developmental delay and the diagnosis of autism was previously established in five of them. Key metabolic findings included reduced NADH production in the presence of phosphorylated carbohydrates (with corresponding increased production in the presence of alternative carbon-based energy sources), increased response to certain hormones (ß-estradiol in particular), and significantly reduced levels of NADH in wells containing tryptophan. The individual analysis revealed no particular differences among the SAS subjects based on molecular findings or phenotypic features. In conclusion, individuals with SAS have a common and recognizable metabolic profile. A lower capacity to utilize glucose as an energy substrate could be contributing to the neurodevelopment phenotype of SAS. The identified abnormalities offer previously unexplored insight into the potential pathophysiology of common SAS phenotypic features.
Assuntos
Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Metabolismo Energético/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Mutação , Fatores de Transcrição/genética , Adolescente , Transtorno do Espectro Autista/metabolismo , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Feminino , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Síndrome , Fatores de Transcrição/metabolismoRESUMO
PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Complexo Repressor Polycomb 2/genética , Síndrome , Sequenciamento do ExomaRESUMO
SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Proteínas de Ligação à Região de Interação com a Matriz/deficiência , Fatores de Transcrição/deficiência , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 2/ultraestrutura , Colágeno Tipo III/deficiência , Colágeno Tipo III/genética , Colágeno Tipo V/deficiência , Colágeno Tipo V/genética , Nanismo/genética , Face/anormalidades , Feminino , Estudos de Associação Genética , Idade Gestacional , Humanos , Hipertensão Pulmonar/genética , Lactente , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Microcefalia/genética , Fenótipo , Magreza/genética , Fatores de Transcrição/genéticaRESUMO
Patients receiving clinical genetics services often navigate emotionally difficult situations and may utilize their faith as a source of support, an aid in decision-making, or a core coping strategy. Although patients have expressed interest in discussing their religious or spiritual (R/S) beliefs with their genetic counselor (GC), GCs may avoid such conversations because they feel they do not have the necessary skills to discuss R/S beliefs (Reis, Baumiller, Scrivener, Yager, & Warren, 2007). This qualitative study explored how GC programs in North America currently prepare their students to discuss R/S matters with their patients. The aims of this study were to identify (1) the R/S topics genetic counseling programs currently cover in the curriculum, (2) how genetic counseling programs evaluate their students within the R/S topics and activities that are included in the curriculum, and (3) the value or importance placed on R/S training by genetic counseling program directors. Leaders of 12 (36%) of the 33 eligible GC programs at the time of the study participated in a semi-structured phone interview. Their responses were coded using open and axial coding techniques and analyzed using grounded theory. Results revealed that R/S issues are often covered during the psychosocial portions of the curriculum through writing assignments, in class exercises, and role plays. Almost all participating programs include information on pastoral care services, but have little to no training about specific R/S beliefs or the use of spiritual surveys. While participating program directors emphasized that it is critical for students to be prepared to hold conversations about patients' R/S beliefs, the strategies used to prepare students are inconsistent and often not evaluated. We provide suggestions for enriching the R/S training in genetic counseling graduate programs in order to prepare students to facilitate discussions around patients' religion and/or spirituality in genetic counseling sessions.
Assuntos
Currículo , Aconselhamento Genético , Religião , Espiritualidade , Adaptação Psicológica , Feminino , Humanos , Masculino , América do Norte , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.
Assuntos
Epilepsia , Doenças Genéticas Inatas , Proteínas de Ligação à Região de Interação com a Matriz/genética , Malformações do Sistema Nervoso , Transtornos do Sono-Vigília , Fatores de Transcrição/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/fisiopatologia , Humanos , Lactente , Masculino , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Estudos Retrospectivos , Fases do Sono/fisiologia , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Síndrome , Adulto JovemRESUMO
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
Assuntos
Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromina 1/genética , Substituição de Aminoácidos , Estudos Transversais , Heterozigoto , Humanos , FenótipoRESUMO
Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.
Assuntos
Actinas/genética , Substituição de Aminoácidos , Arginina , Estudos de Associação Genética , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/genética , Mutação , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Colo/anormalidades , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Fenótipo , Bexiga Urinária/anormalidades , Sequenciamento do Exoma , Adulto JovemRESUMO
SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Animais , Criança , Pré-Escolar , Códon de Terminação , Modelos Animais de Doenças , Feminino , Rearranjo Gênico , Estudos de Associação Genética , Humanos , Masculino , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: To characterize the radiographic dental phenotype of individuals with SATB2-associated syndrome (SAS). MATERIALS AND METHODS: Participants were evaluated by a multidisciplinary team during a concurrent clinic conducted during the 1st international SAS family meeting held in 2017 at a single institution. Whenever possible, panoramic and/or periapical radiographs were obtained in clinic or previously obtained and provided by the caregiver. RESULTS: Of the 37 individuals evaluated, 18 (12 males, median age 8.5 years) underwent radiographic examination. Dental radiographs revealed anomalies in all individuals starting at 2 years of age. The most consistent finding was delayed development of the mandibular second bicuspids (83%) with other common radiographic findings including delayed development of the roots of the permanent teeth (78%), severely rotated (56%) or malformed teeth (44%), and taurodontism (44%). CONCLUSIONS: Dental anomalies are fully penetrant and can be documented radiographically in all individuals with SAS. CLINICAL RELEVANCE: Dental radiographic findings of delayed second premolar development and delayed development of permanent root formation, especially concurrent with findings of taurodontism and malformed teeth, support a clinical suspicion for SAS and should help differentiate SAS from other neurodevelopmental syndromes.
Assuntos
Cavidade Pulpar/anormalidades , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/genética , Adolescente , Criança , Pré-Escolar , Cavidade Pulpar/diagnóstico por imagem , Feminino , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz , Fenótipo , Radiografia Dentária , Radiografia Panorâmica , Síndrome , Fatores de Transcrição , Adulto JovemRESUMO
SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fenótipo , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fácies , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Padrões de Herança , Masculino , Polimorfismo de Nucleotídeo Único , Síndrome , Adulto JovemAssuntos
Craniossinostoses/genética , Craniossinostoses/cirurgia , Craniotomia , Pré-Escolar , Craniossinostoses/diagnóstico , Craniossinostoses/fisiopatologia , Endoscopia , Feminino , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína 1 Relacionada a Twist/genéticaRESUMO
Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Deficiência Intelectual/genética , Mutação/genética , Animais , Encéfalo/patologia , Linhagem Celular , Exoma/genética , Feminino , Ácido Glutâmico/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Fosforilação/genética , Transdução de Sinais/genéticaAssuntos
Encéfalo/patologia , Manchas Café com Leite/complicações , Manchas Café com Leite/patologia , Síndromes Neurocutâneas/complicações , Síndromes Neurocutâneas/patologia , Encéfalo/diagnóstico por imagem , Manchas Café com Leite/diagnóstico por imagem , Manchas Café com Leite/genética , Humanos , Lactente , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Síndromes Neurocutâneas/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaRESUMO
Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a recently described autosomal recessive mitochondrial disease characterized by early onset of neurological symptoms, a biphasic clinical course, and distinctive neuroimaging. Pathogenic variants in the EARS2 gene that encode for mitochondrial glutamyl-tRNA synthetase are responsible for LTBL. Here, we describe the clinical course of an infant diagnosed with an acute crisis of LTBL and severe liver disease. This article illustrates the utility of blood lactate quantification in addition to basic metabolic testing and brain imaging in a child with low tone and poor growth. In addition, this case demonstrates the utility of current genetic diagnostic testing, in lieu of more invasive procedures, in obtaining rapid answers in this very complicated group of disorders.