KANSL1 gene disruption associated with the full clinical spectrum of 17q21.31 microdeletion syndrome.

BACKGROUND: Chromosome 17q21.31 microdeletion syndrome is a multisystem genomic disorder caused by a recurrent 600-kb-long deletion, or haploinsufficiency of the chromatin modifier gene KANSL1, which maps to that region. Patients with KANSL1 intragenic mutations have been reported to display the major clinical features of 17q21.31 microdeletion syndrome. However, they did not exhibit the full clinical spectrum of this disorder, which might indicate that an additional gene or genes, located in the 17q21.31 locus, might also be involved in the syndrome's phenotype. METHODS: Conventional and molecular karyotypes were performed on a female patient with intellectual disability, agenesis of the corpus callosum, heart defects, hydronephrosis, hypotonia, pigmentary skin anomalies and facial dysmorphic features. FISH analysis was conducted for chromosomal breakpoint localization. qRT-PCR was applied for the comparative gene expression of KANSL1 gene in the patient and a control group. RESULTS: Herein, we present the first report of disruption and haploinsufficiency of the KANSL1 gene, secondary to a t(1;17)(q12;q21)dn chromosomal translocation in a girl that also carried a de novo ~289-kb deletion on 16p11.2. KANSL1 gene expression studies and comparative clinical analysis of patients with 17q21.31 deletions and intragenic KANSL1 gene defects indicate that KANSL1 dysfunction is associated with the full spectrum of the 17q21.31 microdeletion syndrome, which includes characteristic facial features, hypotonia, intellectual disability, and structural defects of the brain, heart and genitourinary system, as well as, musculoskeletal and neuroectodermal anomalies. Moreover, we provide further evidence for the overlapping clinical phenotype of this condition with the cardio-facio-cutaneous (CFC) syndrome. CONCLUSIONS: KANSL1 gene haploinsufficiency is necessary and sufficient to cause the full spectrum of the 17q21.31 microdeletion syndrome. We hypothesize that the KANSL1 gene might have an effect on the Ras/mitogen-activated protein kinase (MAPK) pathway activity, which is known to be deregulated in the CFC syndrome. This pathway has a crucial role in the development of the heart and craniofacial morphology, as well as the skin, eye, brain and musculoskeletal systems.

[Incidence of congenital heart disease in navarra (1989-1998)]. / Incidencia de las cardiopatías congénitas en Navarra (1989-1998).

INTRODUCTION AND OBJECTIVES: Congenital cardiopathies are the most common forms of congenital malformation. They occur in between 5.2 and 12.5 in every thousand live births. The aim of this study was to describe the incidence and nature of congenital heart disease in the Spanish region of Navarra during a specified time period (1989-1998). PATIENTS AND METHOD: The study involved all children with congenital heart disease among the 47 783 born in the region in the specified time period. RESULTS: The incidence was 8.96 per thousand live births, with 90% having one of the 10 most common types of cardiac malformation. The accumulative percentage diagnosed was 25.3% in the first 24 hours of life, 45% in the first week, 65% in the first month, and 83.1% during the first year. Some 30.8% of cases of congenital heart disease required invasive treatment: 25.4% underwent surgery and 6.4%, cardiac catheterization. CONCLUSIONS: The incidence of congenital heart disease in Navarra falls within the range reported for developed countries. The level of care provided in this region is good, as demonstrated by existing diagnostic capabilities and treatment provision.

Incidencia de las cardiopatías congénitas en Navarra (1989-1998) / Incidence of congenital heart disease in Navarra (1989-1998)

Introducción y objetivos. Las cardiopatías congénitas son las malformaciones congénitas más frecuentes. Se detectan entre el 5,2 y el 12,5‰ de los recién nacidos vivos. El objetivo del presente trabajo es conocer la incidencia y la evolución de las cardiopatías congénitas en una región concreta de España (Navarra) y en un período determinado (1989-1998). Pacientes y método. Se estudian los casos de cardiopatía congénita detectados entre los 47.783 niños nacidos en dicha comunidad durante el período indicado. Resultados. Se detecta una incidencia de cardiopatías congénitas del 8,96‰ en recién nacidos vivos, el 90% de las cuales corresponde a las 10 malformaciones cardíacas más frecuentes. El porcentaje acumulado de diagnóstico es del 25,3% en las primeras 24 h de vida, del 45% en la primera semana, del 65% en el primer mes y del 83,1% durante el primer año de vida. El 30,8% de las cardiopatías congénitas requiere tratamiento invasivo: un 25,4% necesita cirugía y un 6,4% cateterismo terapéutico. Conclusiones. La incidencia obtenida en Navarra está dentro del intervalo obtenido en los países desarrollados. Tanto la capacidad diagnóstica como el manejo evolutivo de las cardiopatías congénitas hacen de Navarra una comunidad con un nivel asistencial adecuado para dicha enfermedad

Introduction and objectives. Congenital cardiopathies are the most common forms of congenital malformation. They occur in between 5.2 and 12.5 in every thousand live births. The aim of this study was to describe the incidence and nature of congenital heart disease in the Spanish region of Navarra during a specified time period (1989-1998). Patients and method. The study involved all children with congenital heart disease among the 47 783 born in the region in the specified time period. Results. The incidence was 8.96 per thousand live births, with 90% having one of the 10 most common types of cardiac malformation. The accumulative percentage diagnosed was 25.3% in the first 24 hours of life, 45% in the first week, 65% in the first month, and 83.1% during the first year. Some 30.8% of cases of congenital heart disease required invasive treatment: 25.4% underwent surgery and 6.4%, cardiac catheterization. Conclusions. The incidence of congenital heart disease in Navarra falls within the range reported for developed countries. The level of care provided in this region is good, as demonstrated by existing diagnostic capabilities and treatment provision