Population genetics of native shellfish aquaculture species and potential genetic risks of cultivation

Native shellfish aquaculture has many benefits, but interbreeding of hatchery and wild populations may pose genetic risks to wild populations. The type and magnitude of these risks depends in part on the genetic population structure of native shellfish species. Early genetic studies on marine shellfish provided little evidence for such structure. However, recent population genetic studies provide higher resolution, make use of both neutral and non-neutral molecular markers, and suggest some marine shellfish can exhibit population structure and even local adaptation. Here, we present preliminary results on genetic differentiation among populations of Crassadoma gigantea (the purple-hinged rock scallop) and Parastichopus californicus (the giant California sea cucumber), two native species that are currently being developed for aquaculture production in Puget Sound. Data for both species demonstrate high levels of genetic diversity and indications for population structuring by geography. Additionally, data for P. californicus suggest a potential cryptic species. Results will be used in a genetic risk model to quantify risk under multiple management scenarios, which will provide decision support to resource managers and other stakeholders. Our study shows the importance of population structure for genetic risk assessment and the power of combining empirical data, computer modeling and end-user input

Diagnosis of LCHAD/TFP deficiency in an at risk newborn using umbilical cord blood acylcarnitine analysis

Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency

Deletion of GPIHBP1 causing severe chylomicronemia

Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.Fil: Ng, Bobby G.. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Eklund, Erik A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos. Lund University; SueciaFil: Shiryaev, Sergey A.. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Dong, Yin Y.. University of Oxford; Reino UnidoFil: Abbott, Mary Alice. University of Massachusetts Medical School; Estados UnidosFil: Asteggiano, Carla Gabriela. Universidad Católica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Bamshad, Michael J.. University of Washington; Estados UnidosFil: Barr, Eileen. University of Emory; Estados UnidosFil: Bernstein, Jonathan A.. University of Stanford; Estados UnidosFil: Chelakkadan, Shabeed. Monash Children's Hospital; AustraliaFil: Christodoulou, John. Sydney Medical School; Australia. University of Melbourne; AustraliaFil: Chung, Wendy K.. Columbia University; Estados UnidosFil: Ciliberto, Michael A.. University of Iowa; Estados UnidosFil: Cousin, Janice. National Human Genome Research Institute ; Estados UnidosFil: Gardiner, Fiona. University of Melbourne; AustraliaFil: Ghosh, Suman. University of Florida; Estados UnidosFil: Graf, William D.. University of Connecticut; Estados UnidosFil: Grunewald, Stephanie. University College London; Estados UnidosFil: Hammond, Katherine. University of Alabama at Birmingahm; Estados UnidosFil: Hauser, Natalie S.. Inova, Fairfax Hospital Falls Church; Estados UnidosFil: Hoganson, George E.. University Of Illinois At Chicago; Estados UnidosFil: Houck, Kimberly M.. Baylor College of Medicine; Estados UnidosFil: Kohler, Jennefer N.. University of Stanford; Estados UnidosFil: Morava, Eva. Mayo Clinic; Estados UnidosFil: Larson, Austin A.. University Of Colorado Anschutz Medical Campus.; Estados UnidosFil: Liu, Pengfei. Baylor Genetics; Estados Unidos. Baylor College Of Medicine; Estados UnidosFil: Madathil, Sujana. University of Iowa; Estados UnidosFil: McCormack, Colleen. University of Stanford; Estados UnidosFil: Meeks, Naomi J.L.. University Of Colorado Anschutz Medical Campus.; Estados UnidosFil: Papazoglu, Gabriela Magali. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

SCN3A ‐related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation

Objective Pathogenic variants in SCN3A , encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood‐onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A ‐related neurodevelopmental disorder. Methods Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type vs. variant Nav1.3 subunits co‐expressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293 T cells). Results Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4–6 of domains II‐IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. Interpretation Our study defines SCN3A‐ related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis

Physiological Correlates of Volunteering

We review research on physiological correlates of volunteering, a neglected but promising research field. Some of these correlates seem to be causal factors influencing volunteering. Volunteers tend to have better physical health, both self-reported and expert-assessed, better mental health, and perform better on cognitive tasks. Research thus far has rarely examined neurological, neurochemical, hormonal, and genetic correlates of volunteering to any significant extent, especially controlling for other factors as potential confounds. Evolutionary theory and behavioral genetic research suggest the importance of such physiological factors in humans. Basically, many aspects of social relationships and social activities have effects on health (e.g., Newman and Roberts 2013; Uchino 2004), as the widely used biopsychosocial (BPS) model suggests (Institute of Medicine 2001). Studies of formal volunteering (FV), charitable giving, and altruistic behavior suggest that physiological characteristics are related to volunteering, including specific genes (such as oxytocin receptor [OXTR] genes, Arginine vasopressin receptor [AVPR] genes, dopamine D4 receptor [DRD4] genes, and 5-HTTLPR). We recommend that future research on physiological factors be extended to non-Western populations, focusing specifically on volunteering, and differentiating between different forms and types of volunteering and civic participation

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Reporting bias in medical research - a narrative review

Reporting bias represents a major problem in the assessment of health care interventions. Several prominent cases have been described in the literature, for example, in the reporting of trials of antidepressants, Class I anti-arrhythmic drugs, and selective COX-2 inhibitors. The aim of this narrative review is to gain an overview of reporting bias in the medical literature, focussing on publication bias and selective outcome reporting. We explore whether these types of bias have been shown in areas beyond the well-known cases noted above, in order to gain an impression of how widespread the problem is. For this purpose, we screened relevant articles on reporting bias that had previously been obtained by the German Institute for Quality and Efficiency in Health Care in the context of its health technology assessment reports and other research work, together with the reference lists of these articles