RESUMO
OBJECTIVE: To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. STUDY DESIGN: For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology. RESULTS: Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair. CONCLUSIONS: The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.
Assuntos
Nanismo/genética , Sequenciamento do Exoma , Anormalidades Múltiplas/genética , Actinas/genética , Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Criança , Inibidor de Quinase Dependente de Ciclina p57/genética , Proteínas do Citoesqueleto/genética , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Cinesinas/genética , Masculino , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Estudos Prospectivos , Proteínas Repressoras/genética , Fatores de Elongação da Transcrição/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Individuals with Williams Syndrome (WS) have specific auditory characteristics, including hypoacusis and hyperacusis, and music appreciation skills. Little is known about the functionality of the central auditory nervous system (CANS) for sound processing in WS. Thus, the objective of the present study was to evaluate the functionality of the CANS in individuals with WS, based on auditory event-related potentials, as far as cognitive and behavioral aspects are concerned. The study was carried out with 17 individuals, seven females and ten males, between seven and 17 years old, with WS, and 17 individuals with typical development matched by sex and chronological age to individuals with WS. None of these individuals had middle ear impairment or hearing loss. The subjects were evaluated for intelligence quotient, loudness discomfort level, and auditory event-related potentials with Tone Burst stimuli, on the oddball paradigm; the parents also answered the MTA-SNAP-IV questionnaire. Hyperacusis was found in six WS individuals and two individuals with typical development. In the present study, WS individuals present longer latency and reduced amplitude for P1, N1, N2 and P3 components. These results, suggesting a delay and hypoactive responses of the CANS in this syndrome, that cannot be related to the cognitive or behavioral aspects of these individuals, but it indicates a cortical immaturity to process acoustic stimuli.