RESUMO
Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development.
Assuntos
Histona Acetiltransferases/genética , Anormalidades Musculoesqueléticas/genética , Mutação , Anormalidades Urogenitais/genética , Acetilação , Alelos , Animais , Exoma , Éxons , Feminino , Histonas/metabolismo , Humanos , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Masculino , Camundongos , Anormalidades Musculoesqueléticas/enzimologia , Análise de Sequência de DNA/métodos , Anormalidades Urogenitais/enzimologiaRESUMO
Phelan-McDermid or 22q13.3 deletion syndrome is characterized by global intellectual disability, childhood hypotonia, severely delayed or absent speech, features of autism spectrum disorder, without any major dysmorphisms or somatic anomalies. It is typically diagnosed before adolescence and data about adult patients are virtually absent. The expression of its phenotypical characteristics appears to be linearly related to the deletion size. Here, an intellectually disabled geriatric female patient is described with a long history of challenging behaviors in whom Phelan-McDermid syndrome was demonstrated. Detailed analysis of the patient's history and functioning resulted in a psychiatric diagnosis of atypical bipolar disorder and her behavior significantly improved upon maintenance treatment with a mood stabilizing agent. The present article confirms recent findings that atypical bipolar disorder may be part of the psychopathological phenotype of Phelan-McDermid syndrome, reason why careful etiological search is warranted, also in the geriatric population.