Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that ...commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.
We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples.
A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants.
We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.
Unmanned Aerial Vehicles (UAVs), or drones, offer the ability to collect cost-effective fine-scale imagery that is suitable for the capture of concurrent hydrodynamic and faunal data within tidal ...stream environments. This is a necessary stage of information gathering to inform tidal energy device design, advise control and maintenance strategies and better inform environmental consenting processes. For this study a total of sixty-three UAV surveys were undertaken within the Inner Sound of the Pentland Firth, Scotland, UK, over two 4-day periods in 2016 and 2018. The aims of this data collection effort were to characterise bathymetrically driven hydrodynamic features, comprising of kolk-boil distribution, presence, and area, as well as marine life such as seabird distributions, presence, and orientation relative to the flow. To achieve this, a method to extract quantifiable metrics from UAV imagery was required. This paper details the processes and methodology to create a graphical user interface (GUI) to provide these outputs rather than examining specific results. It includes an explanation of the criteria that the GUI needed to meet to be able to process the imagery, a description of the workflow and an explanation of the sub-routines required such as image registration and calibration. The outputs of the GUI, and their relevance to tidal energy developments, are also discussed. Finally, this paper details future work incorporating computer vision techniques to improve the accuracy, reliability, and processing speed of the GUI.
Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic ...hypogonadism has been suggested to overlap with Witteveen-Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing
. Whether hypogonadotropic hypogonadism is due to haploinsufficiency of
or any of the other eight genes present in 15q24 is not known. We report the case of a female patient with delayed puberty associated with intellectual disability, behavior problems, dysmorphic facial features, and short stature, at the age of 14 years. Clinical, laboratory, and imaging assessments confirmed the diagnosis of Kallmann syndrome. Whole-exome sequencing identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016Argfs*6) in
, classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG/AMP) criteria. Reverse phenotyping led to the clinical diagnosis of WITKOS. No other variant was found in the 96 genes potentially related to hypogonadotropic hypogonadism. The analysis of the other contiguous seven genes to
in 15q24 did not reveal any clinically relevant variant. In conclusion, these findings point to
as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome.
Characteristics of turbulent flow around a braided bar are much more complex as compared to the straight and meandering rivers. The impact of a mid-channel bar on the turbulent flow structure has ...been investigated in this research. A new dominance function S
i
,
H
is proposed in this study as a measure of the relative dominance of ejection and sweep events in turbulent flow structure. Occurrence of the kolk-boil phenomenon is observed due to interaction of ejection and sweep events. The kolk-boil phenomenon generates negative pressure gradients which result in suspension of bed sediment particles in the flow domain. The transition probability of bursting event movements is computed using the first Markov chain. A new parameter movement ratio is formulated in this study, which is found to faithfully reflect the fluvial processes of sedimentation and scouring on the channel bed. Acceleration of flow is seen to occur at adjoining regions close to the upstream end of the bar. Due to the presence of the bar, the flow area in its proximity decreases which has caused increment in the velocity at sections located near the upstream end of the mid-channel bar. For model runs with bars, a distinct bulge in the turbulent intensity graph is observed. The mid-channel bar effect is mainly discernible in the lower layers of flow.
Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without ...a molecular diagnosis. Mutations involving the same gene (e.g., FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome (KS), with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive, and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far.
A man with KS associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis or whole exome sequencing.
Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2.
These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these 2 patients with overlapping phenotypes of WITKOS and CHH.
Witteveen-Kolk syndrome (WITKOS; OMIM #613406) is a recently described, rare neurodevelopmental syndrome characterized by mild intellectual disability and a recognizable facial gestalt. WITKOS is ...caused by heterozygous loss-of-function variants in SIN3A. It shares some features with 15q24 deletion syndrome but to date has only been described in a limited number of patients mostly of Northern European ancestry. Here, we report the first patient with Hispanic ancestry to our knowledge diagnosed with WITKOS, who has a novel, truncating variant in the SIN3A gene. Clinical exome sequencing performed in-house using a custom bioinformatics pipeline identified a de novo heterozygous, nonsense variant in SIN3A, c.1015C>T (p.Gln339Ter) that has not been previously described in the literature. This 3-year-old boy with WITKOS demonstrated classic features including mild developmental delay and triangular facies with hypotelorism and deep-set, hooded eyes. This patient supports the currently described phenotype for WITKOS in more diverse populations.
Witteveen–Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by ...loss of function of switch‐insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive–compulsive behaviors, as well as Attention‐Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10–23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social–emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions.
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