RESUMEN
Intellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X-chromosome. The IQSEC2 gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in IQSEC2 have been historically associated with nonsyndromic X-linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic MECP2, FOXG1, CDKL5, and MEF2C gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic-behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in IQSEC2. Here we report two novel IQSEC2 de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that IQSEC2 may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated.
Asunto(s)
Exoma , Asesoramiento Genético , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Factores de Intercambio de Guanina Nucleótido/genética , Discapacidad Intelectual/genética , Mutación , Convulsiones/complicaciones , Secuencia de Aminoácidos , Animales , Preescolar , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Factores de Intercambio de Guanina Nucleótido/química , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Datos de Secuencia Molecular , Linaje , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the TP53 gene. The frequency of germline de novo TP53 mutations is largely unknown; few unequivocal de novo mutations have been reported. METHODS AND RESULTS: Of 341 patients with early onset cancer sent for clinical testing to a national reference laboratory, 75 patients had TP53 germline mutations. Five (7%) de novo mutations were identified, as well as an additional 10 TP53 germline mutations likely to be de novo by family history. The frequency of de novo TP53 mutations in this patient sample is at least 7% and may be as high as 20%. CONCLUSIONS: The possibility that de novo germline TP53 mutations are relatively common has implications for testing and the identification of potential Li-Fraumeni syndrome in patients with little or no family history of cancer.
Asunto(s)
Síndrome de Li-Fraumeni/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Síndrome de Li-Fraumeni/complicaciones , Masculino , Persona de Mediana Edad , Mutación MissenseRESUMEN
BACKGROUND: Breast cancer tumor ablation as part of a multimodality approach in the treatment of breast cancer is the subject of recent interest. This study was conducted to determine if the ability to perform sentinel node biopsy was impaired after thermal-induced ablation of breast cancer. METHODS: We studied patients who had sentinel node biopsy after preoperative focused microwave phased array for breast cancer ablation. RESULTS: Twenty-one patients with T1-T2 breast cancer and clinically negative axilla underwent wide local excision and sentinel node biopsy guided by blue dye and sulfur colloid. Surgery was done an average of 17 days after microwave ablation. Fifteen of 22 patients (68%) had histologic evidence of tumor necrosis. Sentinel lymph node mapping was successful in 19 of 21 patients (91%). Axillary metastases were detected in 42% of cases. CONCLUSIONS: This study documents successful sentinel lymph node mapping for patients treated with antecedent local tumor ablation using focused microwave phased array ablation.