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1.  Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study 
BMJ Open  2014;4(11):e005041.
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.
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.
Genetic services in tertiary care centres in Chile, following patients with 22q11.2 deletion.
Fatality rate and associated factors.
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.
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.
PMCID: PMC4225234  PMID: 25377008
2.  The genetic basis of DOORS syndrome: an exome-sequencing study 
Lancet Neurology  2014;13(1):44-58.
Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.
Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.
26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.
Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.
US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.
PMCID: PMC3895324  PMID: 24291220
3.  Pathogenesis of Preeclampsia: The Genetic Component 
Journal of Pregnancy  2011;2012:632732.
Preeclampsia (PE) is one of the main causes of maternal and fetal morbidity and mortality in the world, causing nearly 40% of births delivered before 35 weeks of gestation. PE begins with inadequate trophoblast invasion early in pregnancy, which produces an increase in oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease, leading to the characteristic clinical manifestation of PE. Numerous methods have been used to predict the onset of PE with different degrees of efficiency. These methods have used fetal/placental and maternal markers in different stages of pregnancy. From an epidemiological point of view, many studies have shown that PE is a disease with a strong familiar predisposition, which also varies according to geographical, socioeconomic, and racial features, and this information can be used in the prediction process. Large amounts of research have shown a genetic association with a multifactorial polygenic inheritance in the development of this disease. Many biological candidate genes and polymorphisms have been examined in their relation with PE. We will discuss the most important of them, grouped by the different pathogenic mechanisms involved in PE.
PMCID: PMC3235819  PMID: 22175024
4.  Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results 
Human genetics  2009;126(6):763-778.
Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.
PMCID: PMC2888886  PMID: 19662435

Results 1-4 (4)