Routinely used Whole Exome Sequencing (WES) in genetic diagnosis for monogenic disorders revealed numerous variants of uncertain significance (VUSs), which poses considerable problems for genetic counselling and clinical management. In fact, many disease-causing variants have been reported to resulting in aberrant gene splicing. Therefore, for VUSs suspected to cause aberrant splicing, additional evidence can be […]
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Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis
Nephrolithiasis results from interaction between genetic and environmental factors. Calcium oxalate is the most common type of kidney stone. We report a novel genetic mechanism causing hyperoxaluria and nephrolithiasis. In one family, we detected a mutation within the SLC26A6 gene that encodes an oxalate transporter. This mutation impairs SLC26A6 function, which normally secretes oxalate in […]
Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants
Individuals carrying mutations in the CDH1 gene have a high likelihood of developing stomach cancer (lifetime risk 24-42%) and breast cancer (lifetime risk about 43-55%). Identification of these individuals through genetic testing is important because these cancers can be prevented by prophylactic surgery or detected early with endoscopy and breast imaging. Current guidelines recommend genetic testing when […]
Long term dormancy in a BRCA1 heterozygote
Germline pathogenic variants in BRCA1 or BRCA2 genes increase the risk of ovarian high grade serous carcinoma, the most common and most lethal subtype of epithelial ovarian cancer. Carriers of these genetic variants are usually offered surgery known as risk-reducing salpingo-oophorectomy (RRSO) where the Fallopian tubes and ovaries are removed. We report the case of […]
CDH1 germline mutations in healthy individuals from families with the hereditary diffuse gastric cancer syndrome
Hereditary diffuse gastric cancer is an inherited cancer predisposition syndrome associated with CDH1 germline mutations. To date, more than 500 mutations are described from different countries, with a particular higher mutation frequency in countries with low incidence for gastric cancer. The distribution of germline mutations sub-types in this inherited cancer susceptibility is rather heterogeneous: missense […]
Impaired social cognition and fine dexterity in patients with Cowden syndrome associated with germline PTEN variants
Cowden syndrome is a genetic disorder related to germline PTEN variants and characterized by increased risk of cancers. These patients sometimes show behaviors considered as maladapted to social norms and conventions. We collected data on 15 patients from a single center in France. We analyzed their abilities in social cognition, considered as cognitive processes involved […]
Multimodal bioinformatic analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles
Loss of TECPR2 function has been implicated in an array of neurodegenerative diseases, but what exactly is that function? Understanding TECPR2 function is essential for developing precision diagnostics and targeted treatment options for TECPR2-related neurodegenerative diseases. Therefore, we leveraged the increasing amounts of functional genomic data to perform a first comprehensive functional characterization of TECPR2. We report that TECPR2 might […]
Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumors: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome
The genetic background of a previously undescribed manifestation in a Gorlin-Goltz syndrome (including skin basal cell carcinomas and multiple developmental abnormalities) patient is presented: two-sided PEComas (perivascular epitheloid cell tumors) next to the adrenal glands. A novel germ-line mutation of the PTCH1 tumor suppressor gene was identified. Surprisingly, the same somatic mutation (a five nucleotide […]
Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts
Swelling of the extremities (lymphoedema) due to underlying abnormalities of the lymphatic system has many causes but can be genetic. We describe 20 patients with a newly defined clinical entity called WILD syndrome (acronym from Warts, Immunodeficiency and Lymphatic Dysplasia). They presented with asymmetrical lymphoedema affecting different body regions including internal organs. Low immunity was […]
Loeys-Dietz and Shprintzen-Goldberg Syndromes: analysis of TGF-β-opathies with craniofacial manifestations using an innovative multi-modality method
Loeys-Dietz and Shprintzen-Goldberg syndromes are caused by mutations along the TGF-beta signaling pathway. Some of the most striking features include craniofacial anomalies. Yet it is very difficult to find a common facial pattern that can be matched to the specific mutation. We used deep clinical examination methods and cutting-edge imaging technology, such as 3D photos […]