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Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7-1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.
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PURPOSE: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs' evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. METHODS: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children's Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the "My Bibliography" tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. RESULTS: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. CONCLUSIONS: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important.
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Asesoramiento Genético , Humanos , Consejeros , Factor de Impacto de la RevistaAsunto(s)
Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Humanos , Cerebelo/diagnóstico por imagen , Anomalías Múltiples/genética , Enfermedades Renales Quísticas/genética , Retina/diagnóstico por imagen , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Fenotipo , GenotipoRESUMEN
The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.
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Epilepsia , ATPasas de Translocación de Protón Vacuolares , Humanos , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Epilepsia/genética , Adenosina TrifosfatoRESUMEN
PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Fenotipo , Trastornos del Neurodesarrollo/genética , Vía de Señalización Wnt/genética , Discapacidad Intelectual/genética , Genómica , beta Catenina/genéticaRESUMEN
BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.
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Trastornos del Metabolismo del Hierro , Humanos , Trastornos del Metabolismo del Hierro/diagnóstico , Trastornos del Metabolismo del Hierro/genética , Psicometría , Estudios Prospectivos , Estudios Retrospectivos , Proteínas Portadoras/genética , Hierro/metabolismo , Evaluación de Resultado en la Atención de SaludRESUMEN
Pathogenic variants in CASK, an X-linked gene that plays a role in brain development and synaptic function, are the cause of both microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XLID) with or without nystagmus. MICPCH is caused by loss of function variants in CASK, typically affects females, and is associated with moderate-to-severe intellectual disability (ID). Additional findings, present in about one-third of individuals, include feeding difficulties, ophthalmologic issues, hypertonicity, epilepsy, and sensorineural hearing loss. Only a few affected males with MICPCH phenotype have been reported and most have had profound developmental disability and intractable epilepsy. The XLID phenotype is typically caused by missense variants and most often manifests in males; carrier females are mildly affected or unaffected. Nystagmus is often present. In total, over 175 patients have been reported in the literature. We now report an additional 11 patients with pathogenic variants in CASK that expand these phenotypes and reported genotype-phenotype correlations.
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Discapacidad Intelectual , Cerebelo/anomalías , Discapacidades del Desarrollo , Femenino , Estudios de Asociación Genética , Guanilato-Quinasas/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Discapacidad Intelectual Ligada al Cromosoma X , Microcefalia , Mutación , Malformaciones del Sistema Nervioso , FenotipoRESUMEN
BACKGROUND: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. METHODS: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. RESULTS: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). CONCLUSIONS: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.
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Trastorno del Espectro Autista/genética , Moléculas de Adhesión Celular/fisiología , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/fisiología , Receptores de Superficie Celular/genética , Semaforinas/fisiología , Adolescente , Adulto , Trastorno del Espectro Autista/fisiopatología , Niño , Preescolar , Estudios de Asociación Genética , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Transducción de Señal/fisiología , Adulto JovenRESUMEN
Undiagnosed genetic disease imposes a significant burden on families and health-care resources, especially in cases with a complex phenotype. Here we present a child with suspected leukodystrophy in the context of additional features, including hearing loss, clinodactyly, rotated thumbs, tapered fingers, and simplified palmar crease. Trio genome sequencing (GS) identified three molecular diagnoses in this individual: compound heterozygous missense variants associated with polymerase III (Pol III)-related leukodystrophy, a 4-Mb de novo copy-number loss including the MYCN gene associated with Feingold syndrome, and a mosaic single-nucleotide variant associated with COL2A1-related disorders. These variants fully account for the individual's features, but also illustrate the potential for superimposed and unclear contributions of multiple diagnoses to an individual's overall presentation. This report demonstrates the advantage of GS in detection of multiple variant types, including low-level mosaic variants, and emphasizes the need for comprehensive genetic analysis and detailed clinical phenotyping to provide individuals and their families with the maximum benefit for clinical care and genetic counseling.
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Discapacidad Intelectual , Deformidades Congénitas de las Extremidades , Microcefalia , Fístula Traqueoesofágica , Colágeno Tipo II , Párpados/anomalías , HumanosRESUMEN
Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities. Although more than 100 cases have been reported in the literature, a comprehensive review has not been performed nor have clinical guidelines been established. Therefore, we describe the clinical features of 16 additional patients, review features of previously reported individuals, and suggest clinical guidelines. Our findings expand the clinical phenotype of T9M, including novel features of amblyopia, astigmatism, corectopia of pupil, posterior embryotoxon, and diaphragmatic eventration. Most patients had prenatal and perinatal issues, particularly from respiratory, growth, and feeding standpoints. Although small birth parameters were common, long-term growth trends varied widely. An association with advanced parental ages was also identified. The spectrum of growth and development was wide, ranging from nonverbal patients to those able to participate in educational programs with age-appropriate peers. The severity of clinical outcomes was unrelated to blood lymphocyte mosaicism levels. Microarray analysis had a higher diagnostic rate compared to standard karyotype analysis and should be utilized if this diagnosis is suspected. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and determine best practices for clinical management.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Trisomía/diagnóstico , Trisomía/genética , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Cromosomas Humanos Par 9/genética , Femenino , Estudios de Asociación Genética/métodos , Pruebas Genéticas , Gráficos de Crecimiento , Humanos , Lactante , Recién Nacido , Masculino , Mosaicismo , Fenotipo , Adulto JovenRESUMEN
Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.
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Craneosinostosis/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Craneosinostosis/patología , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Microcefalia , Hipotonía Muscular/epidemiología , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación , Fenotipo , Adulto JovenRESUMEN
PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Niño , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Convulsiones/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by early onset of severe neurological injury with intracranial calcifications, leukoencephalopathy, and systemic inflammation. Increasingly, a spectrum of neurological dysfunction and presentation beyond the infantile period is being recognized in AGS. The aim of this study was to characterize late-infantile and juvenile-onset AGS. METHODS: We conducted a multi-institution review of individuals with AGS who were older than one year at the time of presentation, including medical history, imaging characteristics, and suspected diagnoses at presentation. RESULTS: Thirty-four individuals were identified, all with pathogenic variants in RNASEH2B, SAMHD1, ADAR1, or IFIH1. Most individuals had a history of developmental delay and/or systemic symptoms, such as sterile pyrexias and chilblains, followed by a prodromal period associated with increasing symptoms. This was followed by an abrupt onset of neurological decline (fulminant phase), with a median onset at 1.33 years (range 1.00 to 17.68 years). Most individuals presented with a change in gross motor skills (97.0%), typically with increased tone (78.8%). Leukodystrophy was the most common magnetic resonance imaging finding (40.0%). Calcifications were less common (12.9%). CONCLUSIONS: This is the first study to characterize the presentation of late-infantile and juvenile onset AGS and its phenotypic spectrum. Late-onset AGS can present insidiously and lacks classical clinical and neuroimaging findings. Signs of early systemic dysfunction before fulminant disease onset and loss of motor symptoms were common. We strongly recommend genetic testing when there is concern for sustained inflammation of unknown origins or changes in motor skills in children older than one year.
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Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Progresión de la Enfermedad , Destreza Motora/fisiología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Adolescente , Edad de Inicio , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Eritema Pernio/etiología , Niño , Preescolar , Dolor Crónico/etiología , Discapacidades del Desarrollo/etiología , Femenino , Fiebre/etiología , Humanos , Hipotermia/etiología , Lactante , Inflamación/etiología , Masculino , Malformaciones del Sistema Nervioso/complicaciones , Estudios RetrospectivosRESUMEN
Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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Histonas , Enfermedades Neurodegenerativas , Animales , Factores de Transcripción Forkhead/genética , Mutación de Línea Germinal , Histonas/genética , Histonas/metabolismo , Humanos , Enfermedades Neurodegenerativas/genética , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoAsunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Azetidinas/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Malformaciones del Sistema Nervioso/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Adolescente , Edad de Inicio , Azetidinas/efectos adversos , Biomarcadores , Niño , Desarrollo Infantil/efectos de los fármacos , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Lactante , Interferones/genética , Interferones/metabolismo , Inhibidores de las Cinasas Janus/efectos adversos , Análisis de los Mínimos Cuadrados , Masculino , Purinas , Pirazoles , Sulfonamidas/efectos adversos , Adulto JovenRESUMEN
There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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Anomalías Craneofaciales/genética , ADN Helicasas/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Adolescente , Adulto , Dominio Catalítico , Niño , Preescolar , Anomalías Craneofaciales/patología , ADN Helicasas/química , Discapacidades del Desarrollo/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/química , Mutación , Fenotipo , SíndromeRESUMEN
BACKGROUND: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain. METHODS: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected. RESULTS: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age. CONCLUSIONS: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.
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Proteínas Portadoras/genética , Enfermedades Desmielinizantes , Discapacidades del Desarrollo , Epilepsia , Trastornos del Metabolismo del Hierro , Distrofias Neuroaxonales , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/fisiopatología , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Epilepsia/diagnóstico , Epilepsia/etiología , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Humanos , Lactante , Trastornos del Metabolismo del Hierro/complicaciones , Trastornos del Metabolismo del Hierro/diagnóstico , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/fisiopatología , Masculino , Persona de Mediana Edad , Distrofias Neuroaxonales/complicaciones , Distrofias Neuroaxonales/diagnóstico , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/fisiopatología , Fenotipo , Secuenciación del Exoma , Adulto JovenRESUMEN
OBJECTIVE: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. METHODS: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. RESULTS: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study. INTERPRETATION: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273.
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Leucoencefalopatías/diagnóstico , Leucoencefalopatías/genética , Análisis de Secuencia de ADN/métodos , Niño , Preescolar , Estudios Cruzados , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Sustancia Blanca/patologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.