Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients.

22q11.2 microdeletion syndrome (22q11.2DS) is the most common microdeletion disorder in humans, with an incidence of 1/4000 live births. It is caused by a heterozygous deletion of 1.5-3 Mb on chromosome region 22q11.2. Patients with the deletion present features that include neuropsychiatric problems, craniofacial abnormalities and cardiovascular malformations. However, the phenotype is highly variable and the factors related to the clinical heterogeneity are not fully understood. About 65% of patients with 22q11.2DS have congenital heart defects (CHD). The main goal of this study was to identify common CNVs in 22q11.2DS patients that could be associated with the incomplete penetrance of CHD. Analysis of genomic DNA from 253 patients with 22q11.2DS using array technology showed an association between a microduplication located in region 17q21.31 and CHD (p-value = 0.023, OR = 2.75, 95% CI = 1.17-7.03). This region includes the first three exons of KANSL1 gene. Bioinformatic analysis showed that KANSL1 and CRKL, a gene in the commonly deleted region of 22q11.2DS, are part of the same regulatory module in a miRNA-mRNA network. These results show that a KANSL1 microduplication, in combination with the 22q11.2 deletion, is associated with increased risk of CHD in these patients, suggesting that KANSL1 plays a role as a modifier gene in 22q11.2DS patients.

Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study.

OBJECTIVE: Chromosome 22q11.2 deletion is the most commonly occurring known microdeletion syndrome. Deaths related to the syndrome have been reported, but the magnitude of death has not been quantified. This study evaluated the deletion's impact on survival and its clinical manifestations in a large cohort of Chilean patients. DESIGN: Demographic and clinical data of individuals with 22q11 deletions diagnosed between 1998 and 2013 were collected from medical records and death certificates. Case fatality rate was calculated and compared with national vital statistics. OR with 95% CI analysis was used to assess the association between clinical manifestations and death. SETTING: Genetic services in tertiary care centres in Chile, following patients with 22q11.2 deletion. OUTCOMES: Fatality rate and associated factors. RESULTS: 59 of 419 patients (14.1%) died during the study period at a median of 3.4 months (range 0 to 32 years of age). Factors associated with death included congenital heart disease (OR 5.27; 95% CI 2.06 to 13.99; p<0.0001), hypocalcaemia (OR 4.27; 95% CI 1.67 to 11.15; p<0.002) and airway malacia (OR 13.37; 95% CI 1.19 to 110.51; p<0.002). Patients with deletions and defects such as tetralogy of Fallot with or without pulmonary atraesia, truncus arteriosus or ventricular septal defect, had a 2.6-fold to 4.6-fold higher death rate compared with nationwide reports for the same types of defects. CONCLUSIONS: In this cohort, we observed a death rate of 14.1%, implying that one in seven patients with 22q11 deletion died during the study period. Significant associations with cardiac defects, hypocalcaemia and airway malacia were observed. Furthermore, the death risk in patients with 22q11 deletion and cardiac defects exceeded the global figures observed in Chile for infants with structurally similar but apparently isolated anomalies. These observations indicate a need to identify patients who may require specific perioperative management to improve survival.

Palate abnormalities in Chilean patients with chromosome 22q11 microdeletion syndrome.

OBJECTIVE: Chromosome 22q11 microdeletion syndrome (del22q11) is the most frequent microdeletion syndrome in humans, with an estimated incidence of 1/4000. It is recognized as a common identifiable cause of cleft palate. We characterized palatal abnormalities in a large cohort of Chilean patients with del22q11. METHODS: Patients with the deletion were evaluated by geneticists and speech pathologists, including nasopharyngoscopy when indicated. Comparisons between groups with and without palatal abnormalities were performed using Fisher's exact test and Mann-Whitney U test. RESULTS: Two hundred and one patients were included in the study. Palate abnormalities were present in 154 patients (76.6%). The most frequent finding was submucous cleft palate (both classic and occult forms) seen in 80 patients (39.8% of the total group). Overt cleft palate or cleft lip/palate was seen in 30 patients (14.9%). Patients without palate abnormalities had significantly greater frequency of congenital heart disease and higher mortality. CONCLUSIONS: Our data show a high frequency of palate abnormalities without significant association with congenital heart disease. The most common types of palate defects seen in this series are usually not evident on physical examination and thus require a high index of suspicion and active evaluation through nasopharyngoscopy.

Descripción de características clínicas del síndrome velocardiofacial / Velo-cardio-facial syndrome: a description of its clinical characteristics

Uno de los síndromes más frecuentes asociados a fisura palatina es el síndrome Velocardiofacial. Sus características involucran aspectos faciales, cardiológicos, psicológicos, ligüísticos y de aprendizaje, que deben ser abordados por equipos multiprofesionales. Internacionalmente el estudio de este síndrome se ha hizo masificando en forma progresiva. En nuestro país son escasos los grupos que manejan e intervienen en esta población. En este contexto es que se hace necesaria una revisión bibliográfica actualizada, que resuma los hallazgos clínicos y algunos aspectos de manejo multiprofesional, desde una perspectiva fonoaudiológica.

Velo-cardio-facial syndrome (VCFS) is one of the most frecuently associated syndromes to cleft palate. It comprises facial, cardiological, psychological, and linguistic disorders as well as learning difficulties which all must be addressed by a multi-professional team. The study of this syndrome has been systematically carried out around the world. In Chile, however, there are only few health-related professionals who work with this patient population. The present article aims at providing an up-to-date review, from a speech pathology point of view, on the clinical finding and on some aspects involved in the clinical management of VCFS.

Evaluación de la insuficiencia velofaríngea: presentación de un protocolo de evaluación para pacientes portadores de fisura labiopalatina / Evaluation of velopharyngeal insufficiency: presentation of an evaluation protocol for carrier patients of labiopalatine fissure

En nuestro medio existe escaso conocimiento acerca de los contenidos y procedimientos de evaluación fonoaudiológica en pacientes fisurados. Actualmente la evaluación se centra en la Insuficiencia Velofaríngea (IVF). En este trabajo se presenta un Protocolo de evaluación fonoaudiológica de la IVF para pacientes portadores de fisura labiopalatina, de administración actual en la unidad de fonoaudiología de la Fundación Gantz, Santiago, Chile. El Protocolo fue sometido a análisis estadísticos preliminares de validez y confiabilidad, encontrándose resultados favorables. Se discuten los aportes, implicancias clínicas y proyecciones de la presentación efectuada.