Journal of Medical Genetics

PurposeScreening for Lynch syndrome in the general population aims to prevent and detect cancers early. However, current clinical guidelines for those with pathogenic variants are largely based on studies of patients with cancer or strong family history. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1, MSH2, MSH6, or PMS2 in the general population. MethodsThis retrospective case-control study utilizes Helix Research NetworkTM data from...

PurposeFragile X syndrome (FXS) is a hereditary genetic condition, caused by the expansion of the trinucleotide CGG repeated over 200 times (full mutation) in the 5UTR (untranslated region) regulatory region of the FMR1 gene, which leads to the absence of FMRP protein. Although the clinical standard genetic confirmation for FXS diagnosis is limited to the repeats, the use of gene sequencing techniques allowed the identification of genetic variants that occur throughout the entire FMR1 gene, incl...

BackgroundColorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Approximately 10% of CRC cases are linked to hereditary germline variants. Understanding regional genetic predispositions is crucial for developing personalized medicine strategies. ObjectiveThis study aims to analyze pathogenic germline variants associated with polyposis and non-polyposis syndromes in individuals from Bahia, Brazil. MethodsA cross-sectional, obser...

Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. A total of 24 patients from 21 Han Taiwanese families were enrolled and underwent comprehensive physical and audiological examination. We applied targeted next-generation se...

IntroductionLynch syndrome (LS) is a hereditary cancer syndrome caused by (likely) pathogenic variants (LP/P) in DNA mismatch repair genes, including MSH6. It is associated with elevated lifetime risks for colorectal cancer (CRC), endometrial cancer (EC), and other malignancies. However, cancer risks specific to MSH6-associated LS, particularly for non-colorectal cancers, remain poorly defined. This study aims to provide refined cancer risk estimates for individuals with MSH6 LP/P. MethodsWe co...

Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers and offered return of results with genetic counseling. We evaluated participants responses to and the clinical utility of the ...

PurposeThe known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious ...

MUTYH-associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenic MUTYH variants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP. Th...

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular dystrophy, caused by the contraction of the D4Z4 repeats on the permissive 4qA haplotype on chromosome 4, resulting in the faulty expression of the DUX4 gene. Traditional diagnostics is based on Southern blot, a time- and effort-intensive method that can be affected by single nucleotide (SNV), and copy number variants (CNV), as well as by the similarity of the D4Z4 repeats located on chromosome 1...

BackgroundCerebral visual impairment (CVI) is the commonest form of paediatric visual impairment in developed countries. CVI can arise from a host of genetic or acquired causes, but there has been limited research to date on CVI in the context of genetic disorders. MethodsWe carried out a retrospective analysis of genotypic and phenotypic data for participants with CVI within the DECIPHER database and 100,000 Genomes Project (100KGP). Results158 individuals with CVI were identified across both...

BackgroundIt is known that gene- and disease-specific evidence domains can potentially improve the capability of the ACMG/AMP classification criteria to categorize pathogenicity for variants. We aimed to include gene-disease-specific clinical, predictive, and functional domain specifications to the ACMG/AMP criteria with respect to MMR genes. MethodsStarting with the original criteria (InSiGHT criteria) developed by the InSiGHT Variant Interpretation Committee, we systematically addressed speci...

Advances in genomic technologies have driven a substantial shift in cancer care. Understanding patients experience of care and their associated outcomes is essential to effectively delivering precision care. These outcomes are usually evaluated through patient reported measures (PRMs), rather than administrative data. We conducted a systematic review of the literature to identify, describe and summarise the PRMs employed when patients with cancer underwent genetic testing. Search terms included ...

IntroductionAlstrom syndrome (ALMS, #203800) is an ultra-rare monogenic recessive disease. This the syndrome is associated with mutations in the ALMS1 gene, which codes for a centrosome structural protein responsible for centrosome cohesion. The type of mutation associated with ALMS is mostly cLOF (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with little success. The d...

APC c.3920T>A; p.Ile1307Lys (I1307K), prevalent in individuals of Ashkenazi Jewish (AJ) origin, has been associated with a modestly increased colorectal cancer (CRC) risk. Clinical recommendations for I1307K heterozygotes vary across countries and expert groups, reflecting differences in population frequencies, modest risk estimates, and limited data in non-AJ individuals. We analyzed UK Biobank data comprising 466,315 individuals (8,727 with CRC), using genomic analysis to classify AJ and non-A...

Heterozygous FOXL2 (non-)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely penetrant eyelid malformation and incompletely penetrant primary ovarian insufficiency (POI). We collected variants from our in-house database, generated via clinical genetic testing and downstream research testing in the Center for Medical Genetics Ghent, Belgium (2001-202...

Oculocutaneous albinism (OCA) is genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and m...

Myelomeningocele (MMC) is the most severe form of an open neural tube defect (NTD) that is compatible with life. The prevalence of MMC in the United States is 1 in 2,500 live births, with the two ethnicities that have the highest occurrence of MMC being Mexican American (MA) and Caucasian American (EA). Research to date has shown that MMC results from a cumulative effect of environmental and genetic factors. Therefore, determining the underlying molecular etiology would be a step toward developi...

Colour agnosia is a disorder that impairs colour knowledge (naming, recognition) despite intact colour perception. Previously, we have identified the first and only-known family with hereditary developmental colour agnosia. The aim of the current study was to explore genomic regions and candidate genes that potentially cause this trait in this family. For three family members with developmental colour agnosia and three unaffected family members CGH-array analysis and exome sequencing was perform...

PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a rare LoF variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly loca...

BackgroundAlthough individually rare, collectively rare diseases are more common than diabetes mellitus. The diagnostic odyssey for rare diseases is typically prolonged. AimWe aimed to hear the voice of rare disease stakeholders to provide evidence for strategies to improve rare disease care in Tasmania, Australia. MethodsMixed methods research with surveys, focus groups, and interviews captured the voice of healthcare consumers with rare disease, their families, and their caregivers, as well ...