Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM

Evaluating the performance of SURFEXv5 as a new land surface scheme for the ALADINcy36 and ALARO-0 models

The newly developed land surface scheme SURFEX (SURFace EXternalisee) is implemented into a limited-area numerical weather prediction model running operationally in a number of countries of the ALADIN and HIRLAM consortia. The primary question addressed is the ability of SURFEX to be used as a new land surface scheme and thus assessing its potential use in an operational configuration instead of the original ISBA (Interactions between Soil, Biosphere, and Atmosphere) scheme. The results show that the introduction of SURFEX either shows improvement for or has a neutral impact on the 2m temperature, 2m relative humidity and 10m wind. However, it seems that SURFEX has a tendency to produce higher maximum temperatures at high-elevation stations during winter daytime, which degrades the 2m temperature scores. In addition, surface radiative and energy fluxes improve compared to observations from the Cabauw tower. The results also show that promising improvements with a demonstrated positive impact on the forecast performance are achieved by introducing the town energy balance (TEB) scheme. It was found that the use of SURFEX has a neutral impact on the precipitation scores. However, the implementation of TEB within SURFEX for a high-resolution run tends to cause rainfall to be locally concentrated, and the total accumulated precipitation obviously decreases during the summer. One of the novel features developed in SURFEX is the availability of a more advanced surface data assimilation using the extended Kalman filter. The results over Belgium show that the forecast scores are similar between the extended Kalman filter and the classical optimal interpolation scheme. Finally, concerning the vertical scores, the introduction of SURFEX either shows improvement for or has a neutral impact in the free atmosphere

Bacterial Infective Stifle Arthritis Secondary to a Migrating Grass Seed Foreign Body in an Adult Dog

An adult neutered male cocker spaniel was presented with a 2-3week history of left pelvic limb lameness, stifle effusion, general malaise and pyrexia. Computed tomography (CT) imaging revealed an irregular tubular tract, extending from the stifle distally to the level of the mid tibial diaphysis, associated with the long digital extensor muscle. Ultrasonography revealed the tract had echogenic contents, however no foreign body could be identified. Following surgical exploration, a grass seed was identified in the medial compartment of the left stifle. Culture of the grass seed and joint capsule tissue yielded growth of Pantoea agglomerans. Following the surgery and subsequent antibacterial and non-steroidal anti-inflammatory medication, the dog made a full recovery to normal activity

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock