Tonne-Kalscheuer syndrome (TOKAS) is a rare disorder with intellectual disability and multiple congenital abnormalities. TOKAS is caused by pathogenic variants in the RLIM gene located on the X-chromosome. Men are affected, while carrier women are usually asymptomatic. Of the 41 patients reported with TOKAS, only 7 antenatal cases were described. We present here 11 antenatal […]
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Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers
BOADICEA is a multifactorial breast cancer risk model for predicting the future breast cancer risk based on the joint effects of cancer family history, lifestyle, hormonal and reproductive risk factors, polygenic risk score and rare pathogenic variants. Here, Yang et al validated for the first time the full multifactorial model in 1,614 BRCA1 and 1,365 […]
Encephalocraniocutaneous lipomatosis phenotype associated with mosaic biallelic pathogenic variants in the NF1 gene
This paper explores a rare congenital condition called encephalocraniocutaneous lipomatosis (ECCL), which affects the eyes, skin and brain. Researchers examined a patient with neurofibromatosis type 1 (NF1), a genetic disorder, who also exhibited the typical features of ECCL. Genetic analysis of brain and other tissues revealed a distinct mosaic pattern of alterations in the NF1 […]
ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death
ZFYVE19 deficiency is known as a unique ciliopathy that only involves liver, presenting as neonatal cholestasis, progressive portal fibrosis and portal hypertension. In this paper, we demonstrated that Zfyve19 knockout mice when unchallenged showed no obvious abnormalities but recapitulated postnatal aspects of ZFYVE19-deficient patient upon exposure to a biliary insult, prompting that ZFYVE19 deficiency might […]
Variant classification changes over time in the clinical molecular diagnostic laboratory setting
Appropriately classifying genetic testing results is necessary for patients to receive proper care. As more information is discovered about certain genes and their variants/mutations, prior classifications can be updated accordingly. We aimed to study the reclassifications of genetic variants from patients seen at hereditary cancer clinics in Ontario. Of the variants included in this study, […]
An expanded targeted preconception screening panel in Israel – findings and insights
We present the results of an Israeli expanded carrier screening panel (IL-ECSP) in a cohort of 10,115 Israeli participants. The IL-ECSP is a curated variant-based targeted preconception screening test, tailored to the diverse Israeli population, including its minorities. Utilizing this panel, we identified 2.6% at-risk couples, almost twice higher than those that would have been […]
Comprehensive genomic filtering algorithm to expose the cause of skewed X chromosome inactivation. The proof of concept in female haemophilia expression
Inherited disorders linked to the X-chromosome, like haemophilia, commonly affect men, whilst carrier women are typically unaffected. X-chromosome inactivation (XCI) is a normal process in women that compensates X-doses with men, where each woman cell silences either the paternal, or maternal X, in similar proportion. Certain genetic factors skewed-XCI generating female cells preferentially silencing only […]
Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein
Mutations in the gene CASK disrupt brain growth and cause global developmental delay, with the hindbrain (including the cerebellum) disproportionately affected. Here we show that the cerebellum, but not forebrain, remains vulnerable to CASK loss throughout life, and surprisingly, certain CASK mutations affect the forebrain without cerebellar involvement. These mutations disrupt a CASK protein conformation that is specific to vertebrates and likely to have distinct molecular function/s. Based on this evidence, we propose that […]
Novel mutation leading to splice donor loss in a conserved site of DMD gene causes Duchenne muscular dystrophy with cryptorchidism
In a landmark study, our team has unveiled crucial insights into cryptorchidism, a prevalent male birth defect where testicles do not descend properly. By examining the genetic blueprint of affected individuals, we identified new and known genes linked to this condition, primarily on the X chromosome, suggesting a pattern of inheritance from the mother. This […]
Pathogenic variant detection rate varies considerably in Male breast cancer families and sporadic cases: minimal additional contribution beyond BRCA2, BRCA1 and CHEK2
Male breast cancer (MBC) affects around 1 in 1000 men and is known to have a higher underlying cause from high and moderate risk gene pathogenic variants (PV) than female breast cancer, particularly in BRCA2. However, most studies only report overall detection rates without assessing detailed family history. We reviewed genetic testing in 204 families […]