From heterotaxy to VACTER-H syndrome: the clinical variability of ZIC3-related disorders

BACKGROUND: The ZIC3 gene functions as a transcription factor in early stages of left-right body axis formation. Mutations in ZIC3 gene cause a variety of clinical manifestations including isolated congenital heart disease (CHD), heterotaxy & other midline CNS, urogenital & hindgut malformations. We report a four generation family with X-linked heterotaxy associated with a deletion of the ZIC3 gene at ...postprin

Haploinsufficiency of SF3B2 causes craniofacial microsomia

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases

Characteristic Cochlear Hypoplasia in Patients with Walker-Warburg Syndrome: A Radiologic Study of the Inner Ear in alpha-Dystroglycan-Related Muscular Disorders

BACKGROUND AND PURPOSE: Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy are α-dystroglycan–related muscular disorders associated with brain malformations and eye abnormalities in which no structural inner ear abnormality has been described radiologically. We collected patients from 6 tertiary pediatric hospitals and reported the radiologic features and frequency of inner ear dysplasias. MATERIALS AND METHODS: Patients previously diagnosed clinicoradiologically with Walker-Warburg syndrome, muscle-eye-brain disease, or Fukuyama congenital muscular dystrophy were included. We recorded the pathogenic variant, when available. Brain MR imaging and/or CT findings were reviewed in consensus, and inner ear anomalies were classified according to previous description in the literature. We then correlated the clinicoradiologic phenotype with the inner ear phenotype. RESULTS: Thirteen patients fulfilled the criteria for the Walker-Warburg syndrome phenotype, 8 for muscle-eye-brain disease, and 3 for Fukuyama congenital muscular dystrophy. A dysplastic cochlea was demonstrated in 17/24. The most frequent finding was a pronounced cochlear hypoplasia type 4 with a very small anteriorly offset turn beyond the normal-appearing basal turn (12/13 patients with Walker-Warburg syndrome and 1/11 with muscle-eye-brain disease or Fukuyama congenital muscular dystophy). Two of 8 patients with muscle-eye-brain disease, 1/3 with Fukuyama congenital muscular dystrophy, and 1/13 with Walker-Warburg syndrome showed a less severe cochlear hypoplasia type 4. The remaining patients without Walker-Warburg syndrome were healthy. The vestibule and lateral semicircular canals of all patients were normal. Cranial nerve VIII was present in all patients with diagnostic MR imaging. CONCLUSIONS: Most patients with the severe α‐dystroglycanopathy Walker-Warburg syndrome phenotype have a highly characteristic cochlear hypoplasia type 4. Patients with the milder variants, muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, more frequently have a normal cochlea or milder forms of hypoplasia

The first reported case of the DRAGON gene deletion in human. A case with a de-novo interstitial deletion of chromosome 5q15-21.1

Chondrodysplasia punctata (CDP) is an etiologically heterogenous condition caused by single gene disorders, chromosome abnormalities, maternal diseases or exposures to teratogens. We report a male fetus with rhizomelic CDP associated with deletion at 5q15-5q21.1. This segment contains the DRAGON gene, a bone morphogenetic factor co-receptor, also known as RGMb (repulsive guidance molecule b). It is postulated that its haplo-insufficiency is associated with the phenotype in this fetus. The mother (30yo, G2P0SA1L0) was referred at 19.3 weeks for abnormal antenatal ultrasound findings of short limbs, short splayed digits, brachycephaly, small cistern magna, hypoplastic inferior cerebellar vermis, micrognathia, multiple intracardiac echogenic foci and 2-vessel umbilical cord. There was no history of maternal disease/ exposures. The pregnancy was terminated at 21 weeks. Autopsy confirmed the ultrasound findings and in addition showed brain hypomyelination with ...postprin

Using Drones to Determine Chimpanzee Absences at the Edge of Their Distribution in Western Tanzania

Effective species conservation management relies on detailed species distribution data. For many species, such as chimpanzees (Pan troglodytes), distribution data are collected during ground surveys. For chimpanzees, such ground surveys usually focus on detection of the nests they build instead of detection of the chimpanzees themselves due to their low density. However, due to the large areas they still occur in, such surveys are very costly to conduct and repeat frequently to monitor populations over time. Species distribution models are more accurate if they include presence as well as absence data. Earlier studies used drones to determine chimpanzee presence using nests. In this study, therefore, we explored the use of drones to determine the absence of chimpanzee nests in areas we flew over on the edge of the chimpanzee distribution in western Tanzania. We conducted 13 flights with a fixed-wing drone and collected 3560 images for which manual inspection took 180 h. Flights were divided into a total of 746 25 m2 plots for which we determined the absence probability of nests. In three flights, we detected nests, in eight, absence was assumed based on a 95% probability criterion, and in two flights, nest absence could not be assumed. Our study indicates that drones can be used to cover relatively large areas to determine the absence of chimpanzees. To fully benefit from the usage of drones to determine the presence and absence of chimpanzees, it is crucial that methods are developed to automate nest detection in images

NSD1 mutations generate a genome-wide DNA methylation signature

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Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2-related disorders

Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.Background Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified. Methods and results We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion. Conclusions Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complicationhe McLaughlin Centre, University of Toronto, Toronto, Canada, and Fondation Jeanne et Jean- Louis Lévesque (JLM). The Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Canada. FDL has a fellowship funded by FCT - Fundação para a Ciência e a Tecnologia (SFRH/BD/84650/2010)info:eu-repo/semantics/publishedVersio

Barriers to chimpanzee gene flow at the south-east edge of their distribution

Populations on the edge of a species' distribution may represent an important source of adaptive diversity, yet these populations tend to be more fragmented and are more likely to be geographically isolated. Lack of genetic exchanges between such populations, due to barriers to animal movement, can not only compromise adaptive potential but also lead to the fixation of deleterious alleles. The south-eastern edge of chimpanzee distribution is particularly fragmented, and conflicting hypotheses have been proposed about population connectivity and viability. To address this uncertainty, we generated both mitochondrial and MiSeq-based microsatellite genotypes for 290 individuals ranging across western Tanzania. While shared mitochondrial haplotypes confirmed historical gene flow, our microsatellite analyses revealed two distinct clusters, suggesting two populations currently isolated from one another. However, we found evidence of high levels of gene flow maintained within each of these clusters, one of which covers an 18,000 km2 ecosystem. Landscape genetic analyses confirmed the presence of barriers to gene flow with rivers and bare habitats highly restricting chimpanzee movement. Our study demonstrates how advances in sequencing technologies, combined with the development of landscape genetics approaches, can resolve ambiguities in the genetic history of critical populations and better inform conservation efforts of endangered species