Genome sequencing in families with congenital limb malformations

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02295-y

PEDIA: prioritization of exome data by image analysis.

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis

Effect of sainfoin (Onobrychis viciifolia) silage and hay against gastrointestinal nematodes in lambs

The objective of the studywas to examine the effect of dried and ensiled sainfoin (Onobrychis viciifolia) on established populations of Haemonchus contortus (abomasum) and Cooperia curticei (small intestine) in lambs under controlled conditions. Twenty-four parasite naı¨ve lambs were inoculated with a single dose of infective larvae of these parasites 28 days prior to the start of the feeding experiment. Twenty-four days post-infection, 4 days prior to the start of the feeding experiment, animals were allocated to four groups according to egg excretion, liveweight and sex. GroupsAandBreceived sainfoin hay and control hay, respectively, for 16 days. Groups CandDwere fed on sainfoin silage or control silage for the same period. Feeds were offered ad libitumand on the basis of daily refusals were supplemented with concentrate in order to make them isoproteic and isoenergetic. Individual faecal egg counts on a dry matter basis (FECDM) were performed every 3–4 days and faecal cultures and packed cell volume (PCV) measurements were done weekly. After 16 days of experimental feeding, all animals were slaughtered and adult wormpopulations were determined. The consumption of conserved sainfoin was associated with a reduction of adult H. contortus (47%in the case of hay, P < 0.05; 49%in the case of silage, P = 0.075) but had little effect on adult C. curticei. Compared to the controls, H. contortus specific FECDM was reduced by 58% (P < 0.01) in the sainfoin hay group and by 48%(P = 0.075) in the sainfoin silage group. For both sainfoin feeds FECDMspecific to C. curticei were significantly decreased when compared to the control feeds (hay 81% and silage 74%, both tests P < 0.001). Our data suggest that different mechanisms were responsible for the reduction in FECDM in response to feeding tanniferous fodder. For H. contortus, the decrease seemed to be due to a nematocidal effect towards adult H. contortus. In contrast for C. curticei, the reduction in FECDM appeared to be a result of a reduced per capita fecundity. For both, hay and silage, an antiparasitic effect could be shown, offering promising perspectives for the use of conserved tanniferous fodder as a complementary control approach against GIN. # 2006 Elsevier B.V. All rights reserved

Breaking ground in cross-cultural research on the fear of being laughed at (gelotophobia): A multi-national study involving 73 countries

The current study examines whether the fear of being laughed at (gelotophobia) can be assessed reliably and validly by means of a self-report instrument in different countries of the world. All items of the GELOPH (Ruch and Titze, GELOPH46, University of Düsseldorf, 1998; Ruch and Proyer, Swiss Journal of Psychology 67:19–27, 2008b) were translated to the local language of the collaborator (42 languages in total). In total, 22,610 participants in 93 samples from 73 countries completed the GELOPH. Across all samples the reliability of the 15-item questionnaire was high (mean alpha of .85) and in all samples the scales appeared to be unidimensional. The endorsement rates for the items ranged from 1.31% through 80.00% to a single item. Variations in the mean scores of the items were more strongly related to the culture in a country and not to the language in which the data were collected. This was also supported by a multidimensional scaling analysis with standardized mean scores of the items from the GELOPH15. This analysis identified two dimensions that further helped explaining the data (i.e., insecure vs. intense avoidant-restrictive and low vs. high suspicious tendencies towards the laughter of others). Furthermore, multiple samples derived from one country tended to be (with a few exceptions) highly similar. The study shows that gelotophobia can be assessed reliably by means of a self-report instrument in cross-cultural research. This study enables further studies of the fear of being laughed at with regard to differences in the prevalence and putative causes of gelotophobia in comparisons to different cultures