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The limited variant analysis, along with a higher-than-expected prevalence of "pathogenic" variants in IEI genes within their population, raises the possibility that many of the variants reported by the authors are not truly clinically significant. In this article, the authors report that 200/330 (61%) of children admitted to the PICU with severe sepsis who underwent exome sequencing (ES) had a clinically significant genetic variant in a gene(s) associated with a known inborn error of immunity (IEI) that may have contributed to the patient's clinical presentation. To the Editor: We read with interest the recent publication by KF Kernan et al., which reported an increased prevalence of potentially pathogenic variants in genes related to monogenic immunologic disorders among children admitted to the pediatric intensive care unit (PICU) with severe sepsis [[1]]. [Extracted from the article]

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription. [ABSTRACT FROM AUTHOR]

Genetic testing is important to augment clinical diagnosis and inform management of inherited arrhythmias syndromes (IAS), but variants of uncertain significance (VUS) are common and remain a challenge in clinical practice. In 2015, American College of Medical Genetics (ACMG) published updated guidelines for interpretation of genetic results. Despite increasing understanding of human genomic variation, there are no guidelines for reinterpretation of prior genetic test results. Patients at a single tertiary children's hospital with genetic testing for an IAS that demonstrated a VUS were re-evaluated using 2015 ACMG guidelines, clinical information, and publically available databases. Search of the electronic medical record identified 116 patients with genetic testing results available, and 24/116 (21%) harbored a VUS for an IAS. 23 unique VUS were evaluated from 12 genes. Over half of the VUS (12/23 (52%)) were reclassified using 2015 criteria, and 8 (35%) changed to pathogenic and 4 (17%) to benign. Relative risk of reclassification of VUS to a pathogenic variant in a patient with confirmed clinical diagnosis was 4.1 (95% CI 1.23–15.4). Reclassification was not associated with initial testing year. These data demonstrate 52% of VUS in children with IAS are reclassified with application of 2015 ACMG guidelines. Strength of phenotyping is associated with eventual pathogenic classification of genetic variants and periodic re-evaluation of VUS identified on genetic testing for IAS is warranted. [ABSTRACT FROM AUTHOR]

Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABAA). Clusters of GABAA receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABAA receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABAA receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant condition with an increased risk of sudden cardiac death. Although clinical genetic testing can be used for confirmation of a clinical diagnosis as well as a predictive test, based on our clinical experience it is underutilized. Therefore, we developed and administered a questionnaire to assess potential determinants of parental interest in this testing. Of the 30 adult caregivers who participated, 80% had heard of genetic testing, whereas only 30% knew about genetic testing specifically for HCM. Once informed of the availability, 62% said they would consider testing in the future and 28% would consider it in the next year. Participants’ younger age, higher education level, knowledge of carrier testing, and positive view of genetic testing were significantly associated with the participant considering HCM genetic testing for their child ( p ≤ 0.05). Based on a logistic regression model, age, education level, and knowing that HCM is an inherited disease were the best predictors of who would consider genetic testing. This study provides healthcare providers with a framework to understand caregivers’ knowledge and views of genetic testing, which can be used to improve clinical care for pediatric HCM patients. [ABSTRACT FROM AUTHOR]

The left ventricular outflow tract (LVOT) malformations aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS) are significant causes of infant mortality. These three malformations are thought to share developmental pathogenetic mechanisms. A strong genetic component has been demonstrated earlier, but the underlying genetic etiologies are unknown. Our objective was to identify genetic susceptibility loci for the broad phenotype of LVOT malformations. We genotyped 411 microsatellites spaced at an average of 10 cM in 43 families constituting 289 individuals, with an additional 5 cM spaced markers for fine mapping. A non-parametric linkage (NPL) analysis of the combined LVOT malformations gave three suggestive linkage peaks on chromosomes 16p12 (NPL score (NPLS)=2.52), 2p23 (NPLS=2.41), and 10q21 (NPLS=2.14). Individually, suggestive peaks for AVS families occurred on chromosomes 16p12 (NPLS=2.64), 7q36 (NPLS=2.31), and 2p25 (NPLS=2.14); and for CoA families on chromosome 1q24 (NPLS=2.61), 6p23 (NPLS=2.29), 7p14 (NPLS=2.27), 10q11 (NPLS=1.98), and 2p15 (NPLS=2.02). Significant NPLS in HLHS families were noted for chromosome 2p15 (NPLS=3.23), with additional suggestive peaks on 19q13 (NPLS=2.16) and 10q21 (NPLS=2.07). Overlapping linkage signals on 10q11 (AVS and CoA) and 16p12 (AVS, CoA, and HLHS) led to higher NPL scores when all malformations were analyzed together. In conclusion, we report suggestive evidence for linkage to chromosomes 2p23, 10q21, and 16p12 for the LVOT malformations of AVS, CoA, and HLHS individually and in a combined analysis, with a significant peak on 2p15 for HLHS. Overlapping linkage peaks provide evidence for a common genetic etiology.European Journal of Human Genetics (2009) 17, 811–819; doi:10.1038/ejhg.2008.255; published online 14 January 2009 [ABSTRACT FROM AUTHOR]

Deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHADD) is a rare inborn error of metabolism. It is associated with hypertrophic cardiomyopathy and less frequently with dilated cardiomyopathy. The incidence and pathophysiology of cardiac involvement in LCHADD is poorly understood. This report describes the acute decompensation of a 3-year-old girl who had LCHADD with rapidly developing dilated cardiomyopathy. A review of the literature and possible causes of cardiomyopathy in LCHADD are explored. [ABSTRACT FROM AUTHOR]

Renal agenesis/adysplasia is the leading etiology of end stage renal disease in children. The etiology for renal agenesis/adysplasia has not been identified. The purpose of the present study was to determine if renal agenesis/adysplasia occur in a familial pattern. Twenty seven cases of bilateral renal agenesis/adysplasia were identified by review of autopsy records, and four were excluded. A male excess of 2.8:1 was noted with a mean gestation of 35 weeks. Prenatal and family histories were obtained on 11/23 families. Potential embryologic stressors were identified in 8/11 pregnancies. Thirty-four 1st and 2nd degree relatives from five families participated in a renal ultrasound exam. An increased prevalence of congenital renal anomalies was identified in the relatives of index patients with bilateral renal agenesis/adysplasia (14.7%) compared to controls (2.2%), with a recurrence risk of 6.2 for 1st degree relatives. The most frequently identified renal anomalies in the family members were solitary kidneys and duplicated collecting systems. The increased prevalence of a range of renal anomalies within affected families raises the possibility that isolated renal malformations result from unidentified gene-environment interactions. [ABSTRACT FROM AUTHOR]

In humans, spontaneous DZ twinning is known to have a genetic basis. A prior investigation in the Flemish and Dutch population showed that the phenotype of ‘having DZ twins’ was consistent with an autosomal monogenic dominant model, with a gene frequency of 3.5% and a female-specific lifetime penetrance of 10%. Recessive, X-linked, polygenic and sporadic models were rejected. This study reports on a genome-wide scan of 14 Flemish families containing 57 mothers of spontaneous DZ twins. Two-point linkage analysis using the autosomal dominant model showed nine chromosomal regions with a LOD score around 1. After multipoint linkage analysis, including heterogeneity, three chromosomes continued to give high LOD scores. These regions were further haplotyped with additional markers at 1 cM distance. The multipoint analysis was not in favour of linkage of the DZ twinning trait in most candidate genes and other regions (LOD score < −2) under the genetic model of autosomal dominance.To further evaluate the evidence for linkage given some uncertainty about the correct mode of inheritance of twinning susceptibility other models of inheritance were tested. Results of this analysis showed all models gave highest LOD scores under dominant models.If heterogeneity among the families is taken into account, the peaks that were observed on chromosome 2, 7 and 18 could well contain a potential gene contributing to DZ twinning. These results give suggestive evidence that the mode of inheritance of DZ twinning is probably more complex than was originally expected.European Journal of Human Genetics (2006) 14, 117–122. doi:10.1038/sj.ejhg.5201522; published online 16 November 2005 [ABSTRACT FROM AUTHOR]