RESUMEN
BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
Asunto(s)
Anomalías Múltiples , Trastorno del Espectro Autista , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Anomalías Dentarias , Masculino , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Anomalías Múltiples/diagnóstico , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/genética , Facies , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN , Proteínas Represoras/genética , Deleción Cromosómica , Fenotipo , Factores de Transcripción/genéticaRESUMEN
We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
Asunto(s)
Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Interferón Tipo I/metabolismo , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Proteínas de Unión al ARN/genética , Adolescente , Adulto , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Biomarcadores/metabolismo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Fenotipo , Adulto JovenAsunto(s)
Catarata/diagnóstico , Catarata/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Mutación , Nucleotidiltransferasas/genética , Escoliosis/diagnóstico , Escoliosis/genética , Alelos , Sustitución de Aminoácidos , Fibroblastos/metabolismo , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , HumanosRESUMEN
AIM: To compare the prevalence of attention deficit disorder and hyperactivity disorder (ADHD) using different diagnostic criteria (DSM-IV-TR versus ICD-10) and two specific scales based on DSM IV (ADHD-IV Rating Scales and SNAP-IV p90) in school-age children (6-12 years). PATIENTS AND METHOD: . A population-based study applying stratified multistage sample design (by courses), proportional to the type of school (public, private and enterd) and demographic areas (rural, city). From a target population of approximately 30 000 subjects a sample of 1509 children. RESULTS: The prevalence rates of ADHD were within the expected range: 3.6% (95% CI = 2.6-4.6%) using DSM-IV criteria, 1.2% (95% CI = 0.6-1.8%) using the ICD-10, 4.6% (95% CI = 3.5-5.7%) using ADHD Rating Scales-IV with a cut-off of 90 percentile 4.11% (95% CI = 3.2-5.1%) using the scale SNAP-IV. However, we found some differences in reference to gender and subtype according to the criteria and instrument used. CONCLUSIONS: We propose to use standard scales, scale by age, sex and evaluator that includes maturation and sociocultural factors help us draw conclusions about the true prevalence of ADHD.