Börjeson–Forssman–Lehmann syndrome: Delineating the clinical and allelic spectrum in 14 new families

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Validation of custom wearable sensors to measure angle kinematics : A technical report

The objective of this study was to determine the accuracy of custom designed wearable sensors when compared to a robotic device to measure i) peak angles in a single plane (flexion/extension) and ii) the extent of error associated with speed of movement. Two experimental procedures were undertaken; i) one wearable sensor was mounted on the arm of a step motor that simulated wrist flexion/extension at the speed of 90°/s with the other wearable sensor static (flat surface); and ii) two wearable sensors were each mounted on a step motor which was programmed to move at two movement speeds 30°/s and 90°/s. When compared to pre-determined angles of the robotic device, the wearable sensors detected peak angles with mean error ranging from -0.95° to 0.11° when one wearable sensor was static and the other dynamic. When two wearable sensors were moving, movement at the higher speed (90°/s) had a mean error range of -2.63° to 0.54, and movement at the slower speed (30°/s) had a mean error range of -0.92° to 2.90°. The custom wearable sensors demonstrated the ability to measure peak angles comparable to the robotic device and demonstrated acceptable to reasonable error when tested at two movement speeds. The results warrant future in vivo testing