Genetic basis of neurodevelopmental disorders in 103 Jordanian families.

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.

Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A.

Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.

How animals distribute themselves in space: variable energy landscapes.

BACKGROUND: Foraging efficiency determines whether animals will be able to raise healthy broods, maintain their own condition, avoid predators and ultimately increase their fitness. Using accelerometers and GPS loggers, features of the habitat and the way animals deal with variable conditions can be translated into energetic costs of movement, which, in turn, can be translated to energy landscapes.We investigated energy landscapes in Gentoo Penguins Pygoscelis papua from two colonies at New Island, Falkland/Malvinas Islands. RESULTS: In our study, the marine areas used by the penguins, parameters of dive depth and the proportion of pelagic and benthic dives varied both between years and colonies. As a consequence, the energy landscapes also varied between the years, and we discuss how this was related to differences in food availability, which were also reflected in differences in carbon and nitrogen stable isotope values and isotopic niche metrics. In the second year, the energy landscape was characterized by lower foraging costs per energy gain, and breeding success was also higher in this year. Additionally, an area around three South American Fur Seal Arctocephalus australis colonies was never used. CONCLUSIONS: These results confirm that energy landscapes vary in time and that the seabirds forage in areas of the energy landscapes that result in minimized energetic costs. Thus, our results support the view of energy landscapes and fear of predation as mechanisms underlying animal foraging behaviour. Furthermore, we show that energy landscapes are useful in linking energy gain and variable energy costs of foraging to breeding success.

Feasibility study of semi-automated measurements of finger joint space widths.

The purpose of this study is to evaluate technical feasibility based on image capturing conditions (film-focus distance (FFD), film sensitivity, film brand, exposure level and tube voltage) that potentially alter radiographs and consequently may influence the semi-automated measurement of joint space distance (JSD) by computer-aided joint space analysis (CAJSA) in rheumatoid arthritis and osteoarthritis. The radiographs of a left hand (deceased man) were acquired under systematically changing image capturing conditions (exposure level: 4-8 mAs; FFD: 90-130 cm; film sensitivity: 200/400 and tube voltage: 40-52 kV with different image modalities: conventional radiographs, original digital radiographs, digital print-outs). All JSD-measurements were performed with the CAJSA-technology (Radiogrammetry Kit, Version 1.3.6; Sectra; Sweden) at the metacarpal-phalangeal articulation. JSD-analysis was not influenced by changes of FFD, exposure level, film sensitivity or film brand. JSD showed significant variation caused by tube voltage (conventional: CV = 1.913% for Agfa and CV = 2.448% for Kodak; digital: CV = 0.741% for Philips print-outs and CV = 0.620% with original digital images versus CV = 2.185% for Siemens print-outs and 0.951% with original digital images). Computer-aided joint space analysis for JSD-measurements is unaffected by the following image capturing parameters: film-focus distance, film sensitivity, film brand and exposure level. An influence of tube voltage was detected in a lesser extent for original digital images compared to the printed digital as well as conventional versions. Consequently, a standardized tube voltage is essential for accurate reproductions of CAJSA-measurements in rheumatoid arthritis and osteoarthritis.

Influence of angulation on metacarpal bone mineral density measurements using digital X-ray radiogrammetry.

OBJECTIVE: Digital X-ray radiogrammetry (DXR) is a computer-assisted technique used to quantify cortical bone density of the metacarpals. The influence of metacarpal bone rotation and type of cast material on bone mineral density (BMD) measurements using the DXR technique was tested. METHODS: The bone mineral density of the hand was measured by DXR, and rotation error (DXR-RE) as coefficients of variation were calculated, to verify reliability and reproducibility of this radiogeometric technique to assess in particular minor disease-related changes in the metacarpal bone mass. The reproducibility of the DXR measurements was also investigated using different cast materials (mull, elastic, and plastic). RESULTS: There were no significant changes in absolute values of DXR-BMD observed between 0 to [Formula: see text] angulation. The relative DXR-RE ranged between 0 % (degree 1) and 0.70 % (degrees 15 and 19) for DXR-BMD. Regarding the different cast materials, DXR-BMD revealed a coefficient of variation with 0.41 % (mull cast) and 0.21 % (elastic cast). For the plastic cast, the DXR technique was not able to perform an analysis of DXR-BMD. CONCLUSION: The study revealed no significant influence of metacarpal rotation on the measurements of metacarpal bone mineral density as estimated by DXR. DXR measurements are not optimal when cast material is used. DXR can accurately quantify periarticular cortical bone mass. This is significant especially for rheumatoid arthritis and related conditions where X-ray imaging of arthritic hands with varying degrees of deformity is performed.

Foraging parameters influencing the detection and interpretation of area-restricted search behaviour in marine predators: a case study with the masked booby.

Identification of Area-restricted search (ARS) behaviour is used to better understand foraging movements and strategies of marine predators. Track-based descriptive analyses are commonly used to detect ARS behaviour, but they may be biased by factors such as foraging trip duration or non-foraging behaviours (i.e. resting on the water). Using first-passage time analysis we tested if (I) daylight resting at the sea surface positions falsely increase the detection of ARS behaviour and (II) short foraging trips are less likely to include ARS behaviour in Masked Boobies Sula dactylatra. We further analysed whether ARS behaviour may be used as a proxy to identify important feeding areas. Depth-acceleration and GPS-loggers were simultaneously deployed on chick-rearing adults to obtain (1) location data every 4 minutes and (2) detailed foraging activity such as diving rates, time spent sitting on the water surface and in flight. In 82% of 50 foraging trips, birds adopted ARS behaviour. In 19.3% of 57 detected ARS zones, birds spent more than 70% of total ARS duration resting on the water, suggesting that these ARS zones were falsely detected. Based on generalized linear mixed models, the probability of detecting false ARS zones was 80%. False ARS zones mostly occurred during short trips in close proximity to the colony, with low or no diving activity. This demonstrates the need to account for resting on the water surface positions in marine animals when determining ARS behaviour based on foraging locations. Dive rates were positively correlated with trip duration and the probability of ARS behaviour increased with increasing number of dives, suggesting that the adoption of ARS behaviour in Masked Boobies is linked to enhanced foraging activity. We conclude that ARS behaviour may be used as a proxy to identify important feeding areas in this species.

Reproducibility and influence of hand rotation on computer-aided joint space analysis.

OBJECTIVES: Computer-aided joint space analysis (CAJSA) is a recently developed, semi-automated tool to aid in the measurement of joint space margins based on hand radiographs. The objective of this study is to verify the potential effect of hand rotation during X-ray imaging on the measurement of joint space width using CAJSA and to evaluate the reproducibility of the CAJSA technique in healthy subjects and in patients with rheumatoid arthritis. METHODS: All joint space distance (JSD) measurements were performed using CAJSA-technology at the metacarpophalangeal articulation based on conventional and digital hand radiographs. RESULTS: I. Hand rotation showed an effect on the reproducibility with CV ranging between 0.39% (angulation 1°) and 1.66% (angulation 19°). II. Regarding the overall reproducibility of the CAJSA method, the intra-radiograph reproducibility of JSD was calculated with CV=0.54% for conventional images and CV=0.38% for digital images. The inter-radiograph reproducibility error was observed with CV=0.66% (conventional images) and CV=0.63% (digital images). III. The study revealed a reproducibility for CAJSA measurements in RA ranging between 0.37% (JSD-MCP ring finger; van der Heijde-modification of the Sharp method score 1) to 1.37% (JSD-MCP index finger; van der Heijde-modification of the Sharp method score 3). CONCLUSION: CAJSA measures JSD at the metacarpophalangeal articulation with high reproducibility in healthy subjects and in patients with differing stages of rheumatoid arthritis. Additional findings show that hand rotation during X-ray imaging has an impact on the CAJSA measurements; thus avoiding acquisition of hand radiographs with a rotation error of more than 15 degrees can be recommended.