Autosomal recessive primary microcephaly (MCPH) is a static neurodevelopmental disorder characterized by congenital small head circumference and non-progressive intellectual disability without additional severe brain malformations. MCPH is a genetically heterogeneous disorder. Sixteen genes (MCPH1-MCPH16) have been discovered so far, mutations thereof lead to autosomal recessive primary microcephaly. In a family, segregating MCPH in an autosomal recessive manner, genome-wide homozygosity mapping mapped a disease locus to 16.9-Mb region on chromosome 12q24.11-q24.32. Following this, exome sequencing in three affected individuals of the family discovered a splice site variant (c.753+3A>T) in citron kinase (CIT) gene, segregating with the disorder in the family. CIT co-localizes to the midbody ring during cytokinesis, and its loss of expression results in defects in neurogenic cytokinesis in both humans and mice. Splice site variant in CIT, identified in this study, is predicted to abolish splice donor site. cDNA sequence of an affected individual showed retention of an intron next to the splice donor site. The study, presented here, revealed the first variant in the CIT causing MCPH in the family.

We need to look out for cardiomyopathy among infants with hypocalcemia. For prevention maternal supplementation during pregnancy and lactation with up to 2000 units of vitamin D and 400 units for their infants.

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BACKGROUNDAutosomal recessive primary microcephaly (MCPH) is a clinically and genetically heterogeneous disorder. Patients with MCPH exhibit reduced occipito-frontal head circumference and non-progressive intellectual disability. To date, 17 genes have been known as an underlying cause of MCPH in humans. ASPM (abnormal spindle-like, microcephaly associated) is the most commonly mutated MCPH gene.OBJECTIVEIdentify the genetic defect underlying MCPH in a Saudi family.DESIGNA cross-sectional clinical genetic study of a Saudi family.SETTINGMadinah Maternity and Children Hospital and Centre for Genetics and Inherited Diseases, Taibah University.PATIENTS AND METHODSA molecular analysis was carried out on DNA samples from 10 individuals of a Saudi family segregating MCPH. DNA was isolated from the peripheral blood of 10 individuals, including 2 patients, and whole exome sequencing was performed using the Nextera Rapid Capture kit and NextSeq500 instrument. VariantStudio was used to filter and prioritize variants.MAIN OUTCOME MEASURE(S)Detection of mutation in the ASPM gene in a family segregating autosomal recessive primary microcephaly.RESULTSA novel homozygous splice-site variant (c.3742-1G>C) in the ASPM gene was identified. The variant is predicted to have an effect on splicing. Human Splice Finder, an in silico tool, predicted skipping of exon 16 due to this variant.CONCLUSIONSkipping of exon 16 may change the order and number of IQ motifs in the ASPM protein leading to typical MCPH phenotype.LIMITATIONSSingle family study.

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Objectives:To investigate the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and rheumatic heart disease (RHD) in Saudi patients.Methods:A case-control study was conducted in Saudi RHD patients. Genomic DNA was isolated from 99 RHD patients attending the Pediatric Cardiology Clinic at the Maternity and Children Hospital, Al-Madinah, Saudi Arabia from March 2013 to June 2014, and from 145 age- and gender-matched controls. Patient clinical records were reviewed to report major and minor modified Jones’ criteria for diagnosis. The diagnosis was confirmed by echocardiography. The ACE I/D polymorphism was identified by polymerase chain reaction.Results:A significant difference in ACE D allele carriage (DD+ID) distribution between RHD cases and controls was identified (p=0.02, odds ratio = 3.6, 95% confidence interval: 1.2-10.8). The D allele carriage was significantly associated with development of mitral valve lesions alone (p=0.03).Conclusion:The ACE I/D polymorphism is associated with an increased risk of RHD in the Saudi population. Further studies are needed to confirm our findings and to understand the molecular mechanisms underlying this association.

Objectives: We studied these predictors at a single cardiac center. Methods: A retrospective cohort study was carried out after obtaining approval from the institutional review board. All patients (age, 0-14 years) who underwent congenital heart disease (CHD) surgery from January 2014 to June 2016 were included. Prolonged mechanical ventilation (PMV) was defined as >72 hours of ventilation. Results: A total of 257 patients were included, among whom 219 (85.2%) were intubated for >72 hours and 38 (14.8%) were intubated for ≥72 hours. Age (29.9 versus 11.95 years), weight (9.6 versus 5.9 kg), cross-clamp time (CCT) (53.6 versus 71.8 min), cardiopulmonary bypass time (CBP) (80.98 versus 124.36 min), length of stay in the pediatric intensive care unit (PICU) (10.4 versus 27.2 days), infection (12.8% versus 42.1%), open sternum (0.9% versus 13.2%), re-intubation (19.2% versus 39.5%), pulmonary hypertension (10.9% versus 31.6%), and impaired heart function (10.1% versus 23.7%) were associated with PMV. In terms of Risk Adjustment in Congenital Heart Surgery (RACHS) classification, only patients with RACHS 4 (18.4%) were associated with the risk for PMV. Conclusions: Age, weight, CBP, CCT, pulmonary hypertension, impaired cardiac function, and sepsis are risk factors for PMV. These factors should be considered when deciding surgery and in providing PICU care.

Down syndrome (DS) is the most common autosomal chromosome anomaly. DS is frequently associated with congenital heart disease (CHD). Patients with DS have 40-60% chance of having CHD. It means that CHD in DS is not only due to trisomy 21 and there are some other genetic factors underlying CHD in DS children. In this study, a total of 240 DNA samples from patients were analyzed including 100 patients with CHD only, 110 patients having CHD along with DS and 30 patients with isolated DS. A cardiovascular gene panel consisting of probes for 406 genes was used to screen DNA samples of all 240 patients for mutation identification. All variants were annotated and common variants were obtained. Briefly, 28 common variants (variants common in two or more than two individuals) were obtained in a group of samples containing DNA from DS patients having CHD as well, 63 variants were found to be unique to DS group of samples and 73 variants have been identified in patients with CHD only. In order to identify genomic variations determining the risk for CHD in DS, only those variants present in DS-CHD group and absent in isolated CHD and/or isolated DS group were considered for further analysis. Variants specific to DS-CHD group were further evaluated based on expression and function data and pathogenicity of the variant of interest. We have implicated mutations in GATA3, KCNH2, ENG, FLNA, and GUSB genes as an underlying risk factor for CHD in DS patients.