ABSTRACT
Congenital heart disease (CHD) is the most common congenital anomaly, with an overall incidence of approximately 1% in the United Kingdom. Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes-CDK13, PRKD1, and CHD4, in patients with syndromic CHD. PRKD1 encodes a serine/threonine protein kinase, which is important in a variety of fundamental cellular functions. Individuals with a heterozygous mutation in PRKD1 may have facial dysmorphism, ectodermal dysplasia and may have CHDs such as pulmonary stenosis, atrioventricular septal defects, coarctation of the aorta and bicuspid aortic valve. To obtain a greater appreciation for the role that this essential protein kinase plays in cardiogenesis and CHD, we have analysed a Prkd1 transgenic mouse model (Prkd1em1 ) carrying deletion of exon 2, causing loss of function. High-resolution episcopic microscopy affords detailed morphological 3D analysis of the developing heart and provides evidence for an essential role of Prkd1 in both normal cardiac development and CHD. We show that homozygous deletion of Prkd1 is associated with complex forms of CHD such as atrioventricular septal defects, and bicuspid aortic and pulmonary valves, and is lethal. Even in heterozygotes, cardiac differences occur. However, given that 97% of Prkd1 heterozygous mice display normal heart development, it is likely that one normal allele is sufficient, with the defects seen most likely to represent sporadic events. Moreover, mRNA and protein expression levels were investigated by RT-qPCR and western immunoblotting, respectively. A significant reduction in Prkd1 mRNA levels was seen in homozygotes, but not heterozygotes, compared to WT littermates. While a trend towards lower PRKD1 protein expression was seen in the heterozygotes, the difference was only significant in the homozygotes. There was no compensation by the related Prkd2 and Prkd3 at transcript level, as evidenced by RT-qPCR. Overall, we demonstrate a vital role of Prkd1 in heart development and the aetiology of CHD.
ABSTRACT
BACKGROUND: Esophageal atresia is a developmental disorder in which the upper and lower esophagus fail to connect. It has an estimated prevalence of 1 in 2,500-4,500 live births and has poorer outcomes in low- and middle-income countries than in high-income countries. This study focused on the disorder's epidemiology, morbidity, and mortality in Jordan to address the lack of data regarding esophageal atresia in this country. METHODS: This was a retrospective study covering a 16-year period at a tertiary care academic hospital. Data were extracted from archived medical records and operative notes. All patients who had complete congenital esophageal atresia data were included. In total, the records of 55 patients were analyzed. RESULTS: Of the included patients, 9% were diagnosed prenatally and 47% were diagnosed with polyhydramnios. The mean gestational age was 37 weeks, the mean birthweight was 2,550 g, and 60% of patients were male. Isolated cases of esophageal atresia were reported in 58.2% of patients. There was a high rate of associated congenital anomalies (41.8%), with cardiac lesions the most common (20%), and 5.5% were syndromic. Parental consanguinity was found in 18.2% of patients. Postoperative surgical-related morbidities included stricture (18/24; 75%) and leakage (5/24; 20.8%). Fistula recurrence occurred in one patient (4.2%). The mortality rate was 12.8%. CONCLUSION: Esophageal atresia causes a high rate of mortality and exhibits post-operative morbidities. Moreover, associated anomalies were frequently observed. A high level of the malformation was found among offspring from consanguineous marriages.
