Pathogenic variants in BARD1, RAD51C and RAD51D have recently been established as breast cancer susceptibility genes; and pathogenic variants in PALB2 have been shown to be associated with epithelial ovarian cancer risk. No cancer risk prediction model currently exists which incorporates these associations. Here, the BOADICEA multifactorial breast and ovarian cancer risk prediction model was […]
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Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases
A 313-variant-based polygenic risk score (PRS) is shown to stratify women from breast cancer families into different clinically relevant risk categories. Adding this PRS to family history-based risk prediction would have changed screening advise for 1 out of 3 women diagnosed with breast cancer (BC) at a young age or with a positive family history. […]
Patient-facing Digital Tools for Delivering Genetic Services: A Systematic Review
Digital tools are used to increase patient access and efficiency in genetic services. We reviewed outcomes of patient-facing digital tools used across the genetic testing journey. Our review found that digital tools can improve patient outcomes and system efficiencies. However, most existing tools are developed for the pre-test phase and cancer setting, limiting our understanding […]
Systems approach to enhance Lynch syndrome diagnosis through tumour testing
Colorectal cancer tumor testing is recommended to pre-screen patients to determine who should undergo genetic testing to rule out Lynch syndrome, the most common colorectal cancer syndrome. However, compliance is low and most patients with abnormal results do not undergo Lynch syndrome screening. We developed a systems approach that was eventually automated to increase referral for genetic […]
Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome
The Retriever subunit VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after WASHC5 and CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This report expands the clinical spectrum of patients with pathogenic VPS35L variants, and identifies both overlapping and distinctive features […]
Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
Truncating mutations in MAGEL2, which lead to a shortened protein, cause Schaaf-Yang syndrome (SYS). We have compiled all reported cases and provide Clinical Management Recommendations to help families and physicians manage these patients. We have further characterized the cellular effects of these mutations. We have introduced a normal (full) or truncated form of the gene […]
A founder UMOD variant is a common cause of hereditary nephropathy in the British population
In this study, we report the unexpected finding of an unusual UMOD variant (c.278_289delTCTGCCCCG AAG insCCGCCTCCT) in multiple pedigrees within the British population, all of White British ancestry, from a wide geographical distribution across the UK. A common extended haplotype indicative of an ancestral variant was identified within 1Mb of the UMOD variant in all individuals undergoing genome sequencing through […]
TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation
Bi-allelic pathogenic variants in the TMPRSS3 gene result in non-syndromic deafness at the DFNB8/10 locus. TMPRSS3-realted hearing loss is a common form of congenital deafness in humans. Although two decades have passed since TMPRSS3 was casually linked to deafness, its expression in the inner ear and the best course of clinical intervention for individuals with […]
CDKN1C hyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inherited KCNQ1OT1:TSS-DMR
CDKN1C is a negative regulator for cell proliferation. KCNQ1OT1:TSS-differentially methylated region (DMR) resides on chromosome 11p15.5 and regulates CDKN1C expression via KCNQ1OT1 expression. Paternal deletions involving the KCNQ1OT1:TSS-DMR result in variable phenotypes. However, expression analyses for CDKN1C in these patients are very limited. We identified two patients with prenatal and postnatal growth failure and clinical […]
Axenfeld-Rieger syndrome: more than meets the eye
Axenfeld-Rieger syndrome (ARS) is a rare eye syndrome which has been known for 100 years but remains incompletely understood. Through analysis of 128 individuals with genetically confirmed ARS, we expand the spectrum of clinical features associated with this disorder and identify De Hauwere syndrome as a type of ARS. The two main genetic causes result […]