RESUMO
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.
Assuntos
Disceratose Congênita/diagnóstico , Disceratose Congênita/genética , Exoma/genética , Variação Genética/genética , DNA Ligase Dependente de ATP/genética , Proteínas de Ligação a DNA/genética , Humanos , Linhagem , Diester Fosfórico Hidrolases/genética , Análise de Sequência de DNA , Síndrome , Fatores de Transcrição/genéticaRESUMO
BACKGROUND & AIM: plasma amino acid levels may show differences in regard to physiological changes, diet and diseases. The aim of the study is to measure the amino acid levels in children with celiac disease and compare them with the controls. MATERIAL AND METHODS: sixty-two children with classic celiac disease and 62 age and sex matched healthy control were enrolled in this study. Plasma amino acid levels of the children were measured by using tandem mass spectrometry. RESULTS: celiac children had significant lower plasma levels of citrülline, glutamine and cystine than control (p.
Antecedentes y objetivo: los niveles de aminoácidos en plasma pueden mostrar diferencias en lo que se refiere a los cambios fisiológicos, la dieta y las enfermedades. El objetivo del estudio es medir los niveles de aminoácidos en los niños con enfermedad celíaca y compararlos con los controles. Material y métodos: en este estudio se inscribieron 62 niños con enfermedad celíaca clásica emparejados por edad y sexo con 62 controles sanos. Los niveles de aminoácidos en plasma de los niños se midieron utilizando la espectrometría de masas. Resultados: los niños celíacos tenían niveles significativamente inferiores plasmáticos de citrulina, glutamina y cistina que el grupo control (p < 0,05). Alanina, asparagina, ácido glutámico, hidroxiprolina, isoleucina, leucina, fenilalanina, prolina, serina, treonina y valina fueron significativamente mayores en los niños celíacos que en los controles (p < 0,05). Por otro lado, no hubo ninguna diferencia significativa en los niveles de arginina, argininosuccinato, ácido aspártico, glicina, homocisteína, lisina, hidroxilisina, metionina, ornitina, triptófano, tirosina, histidina entre los niños celíacos y los controles sanos (p > 0,05). Conclusiones: este estudio mostró que los niveles de aminoácidos en plasma pueden ser variables en la enfermedad celíaca. Se necesitan estudios con un tamaño mayor para conocer si los ensayos de aminoácidos en plasma ayudan a reflejar la lesión de la mucosa intestinal y para el seguimiento de la compatibilidad de la dieta libre de gluten en los pacientes celíacos.