Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities.

PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.

Habitat suitability modelling of Koklass pheasant (Pucrasia macrolopha) in moist temperate forest.

The decreasing status of on IUCN of Koklass pheasant (Pucrasia macrolopha) belongs to the family Phasianidae and the order Galliform needs the attention of researchers. The species with habitats as low as 6,000 feet and as high as 11,000 feet certainly cover a broad variety of habitats, such a wide altitude range embraces a diverse range of habitats. Insufficient research has been conducted on the suitability of moist temperate forests as a potential habitat for the Koklass pheasant. Therefore, this study was carried out to explore habitat suitability in 15 different sites which were located in the 4 districts of Hazara Division using GIS data science and environmental variables. A random sampling technique was used for laying out the transect. Overall, 45 line transects (Length 2-4 km, Width 10-30 m) were laid out in study sites. The size of sample plots for trees was 10x10m, for shrubs (4 x4m), and herbs and grasses 1x1m. The other habitat parameters like elevation, slope, cover, and frequency of plant at each point were also considered. We found the uneven distribution of Koklass pheasant in the Hazara Division. There were 59 occurrence points identified and highlighted the distribution of Koklass pheasant in the study area. Although all environmental variables were preferred by Koklass pheasant in its habitat statistical analysis proved that slope, level of disturbance, tree and shrub frequency of habitat contributed mostly to the presence of Koklass in each study site except the contribution of soil and herbs. The potential suitable habitat of Koklass pheasant was estimated to be 439.6 km2 areas starting from Abbottabad to Mansehra in the Hazara division. Awareness and enforcing legal protection are recommended for the conservation of Koklass Pheasant in Moist temperate forest.