Most genes linked to inherited diseases follow either a dominant or recessive pattern, but some genes can cause disease through both modes. This study investigated these unusual “dual-inheritance” genes. The researchers compiled a list of 562 such genes and identified key features that set them apart, and other features that were intermediate between the two […]
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Mixed functional consequences of the N651D GRIA3 variant: a case of early-onset developmental and epileptic encephalopathy with Parkinsonism
Our study focuses on a rare genetic change in the GRIA3 gene, which plays a key role in excitatory brain pathways. This gene encodes a protein that is part of the AMPA receptor. We discovered a new variant in a child with severe developmental problems, epilepsy, and movement disorders. Interestingly, this mutation does not fit […]
Inefficiencies in precision medicine: can genetic counsellors (GC) be the solution? The experience from the first GC-led cancer genetics service in Asia
Utility of genetic testing (GT) to guide cancer treatment, risk management and prevention, has driven the demand for cancer genetic services. We evaluate the outcomes of the first Genetic Counsellor (GC)-led service in Asia, as a potential model for mainstreaming. GC efforts were significant in addressing barriers, which led to improved uptake and increased carrier […]
Multiple early onset atypical cutaneous fibrous histiocytomas in multilocus inherited neoplasia allele syndrome involving TP53 and FLCN genes
A 16-year-old boy developed multiple rare skin tumours called atypical cutaneous fibrous histiocytomas (ACFHs). Genetic testing revealed he has two inherited cancer predisposition conditions: Li-Fraumeni syndrome (TP53 gene) and Birt-Hogg-Dubé syndrome (FLCN gene), a rare combination known as MINAS. His TP53 mutation was new (not inherited), while the FLCN mutation came from his father. This […]
Long-term efficacy of migalastat in females with Fabry disease
Females with Fabry disease often experience diagnostic delays and underappreciated disease burden due to variable disease presentation and progression. The spectrum of disease severity and long-term efficacy of migalastat were assessed in females with Fabry disease and amenable GLA variants. Most had multiorgan involvement at baseline, suggesting significant disease burden. Migalastat treatment preserved renal function, […]
APC I1307K and clinical management: insights from UK Biobank association analysis of colorectal and other cancer risks in Ashkenazi and non-Ashkenazi whites
The APC I1307K variant, more common in Ashkenazi Jewish (AJ) individuals, has been linked to a modest increase in colorectal cancer (CRC) risk. Analysis of over 460,000 UK Biobank participants found no statistically significant association between I1307K and CRC—or other cancers—in AJ or non-AJ white populations. However, the analysis was underpowered due to the variant’s […]
Resolving structural variations missed by short-read sequencing uncovers their pathogenicity
Short-read Genome sequencing (sr-GS) affords efficient characterization of apparently balanced chromosomal rearrangement. However, 9 to 11% of cases remain undetectable, mainly due to highly repetitive genomic regions at breakpoints. We studied 14 patients with abnormal phenotype carrying ABCR that could not be detected by sr-GS. We used a combination of different approaches including fluorescence in […]
Development of a functional assay for the characterisation of SMAD4 variants from the French haemorrhagic hereditary telangiectasia cohort
Hereditary Hemorrhagic Telangiectasia (HHT) and Juvenile Polyposis Syndrome (JPS) can be caused by deleterious variants in the SMAD4 gene, which is part of the TGFß/BMP signaling pathway. We developed a functional assay for SMAD4 variants that allows discrimination between benign and pathogenic SMAD4 variants. We found that all the variants tested led to a loss of function in the SMAD4 protein. […]
First intragenic inversion of CYP11B1 gene causing 11β-hydroxylase deficiency: a molecular diagnosis easily overlooked
Steroid hormones are essential for the body to function properly. 11beta-hydroxylase deficiency is a rare genetic disorder that disrupts the production of steroid hormones. We have studied a patient with this deficiency and have identified a structural anomaly in the CYP11B1 gene in this family, which is particularly complicated to identify: the region of the […]
Homologous recombination deficiency in unselected high-grade ovarian carcinoma
1008 women with high-grade ovarian carcinoma (serous, endometrioid, clear cell, carcinosarcoma) were tested for pathogenic variants (PV) in germline homologous recombination repair (HRR) genes and tumour homologous recombination deficiency (HRD) including tumour BRCA1/2 and genomic instability (GI). Over 95% of tumours with a BRCA1 PV had High GI, whilst only 80% with a BRCA2 PV […]