Recent articles in JMG exemplify a broader shift from cataloguing gene-disease associations to estimating clinically calibrated variant effects. Large sequencing cohorts are coupled with deep clinical characterisation to (1) delineate how inherited variants contribute to adult disease risk (https://jmg.bmj.com/content/early/2026/02/10/jmg-2025-111201), (2) expand and refine genotype-phenotype relationships for rare neurodevelopmental and syndromic conditions (https://jmg.bmj.com/content/early/2026/01/29/jmg-2025-111027; https://jmg.bmj.com/content/early/2026/01/28/jmg-2025-111040), and (3) […]
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Reclassification of variants of uncertain significance in type 1 collagen genes: a national reference laboratory experience (Contributed by Professor Meena Balasubramanian)
Osteogenesis Imperfecta (OI) is an important condition to diagnose early to ensure children are monitored and treated in a timely manner. Increased access to genetic testing has enabled more diagnosis but this can be complicated by ‘Variants of uncertain significance (VUS)’ which results in uncertainty. Using England’s national OI database, we undertook an iterative analysis […]
Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension (Contributed by Carrie L Welch)
Pulmonary arterial hypertension (PAH) is a rare blood vessel disorder that can be fatal. The development of PAH in early childhood, often accompanied by other medical issues, is likely caused by genetic factors but few of the underlying genes have been identified. By connecting doctors and researchers around the world, we identified MECOM, a master regulator […]
MITF (p.E318K) and renal cell carcinoma: current evidence does not support an effect (Contributed by Drs. Eiríkur Steingrímsson and Valentin Yves Walker)
Variants in the human genome are known to predispose to disease. The E318K variant in the MITF transcription factor increases the likelyhood of melanoma whereas the link to renal cancer is inconsistent between studies. In the largest study to date, Walker and colleagues analysed the link between the E318K variant in MITF and renal cancer […]
Biallelic TTBK1 variant causes a severe syndromic neurodevelopmental disorder: clinical and genetic insights from two siblings (Contributed by Zehra Manav Yigit, MD)
Rare genetic conditions affecting brain development are often difficult to diagnose, especially when the responsible gene has previously been studied only in adult brain diseases. In this study, we describe two siblings with a severe neurodevelopmental disorder caused by a loss-of-function change in the TTBK1 gene. TTBK1 is best known for its role in Alzheimer’s disease and other neurodegenerative […]
Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies (Contributed by Dr. Lucia N. Moro)
Desmin (DES) is a key protein that helps muscle cells maintain their structure and function. In this study, we identified and characterized a previously unknown mutation in DES in an Argentine family affected by a muscle disease. Unlike most known DES mutations, this alteration is a small insertion whose disease-causing role was unclear. By combining […]
Refining the phenotypic spectrum of PNKP-related microcephaly: a study of 27 new patients (Contributed by Professor Ghada M H Abdel-Salam)
Primary microcephaly are genetic conditions that are characterized by small head circumference at birth and always associated with intellectual disability. However, early-onset seizures are prevalent in PNKP-related microcephaly. In this study, we present the clinical and molecular genetics findings of 27 patients carrying biallelic PNKP variants. Our findings showed that hypoplastic frontal lobe when associated […]
Obstetric history of women with m.3243A>G: an observational cohort study (Contributed by Dr. Mika Martikainen)
Mitochondrial disease is a common type of inherited metabolic disease, typically caused by pathogenic variants in the maternally inherited mitochondrial DNA (mtDNA). In this study, we investigated a cohort of Finnish women harbouring the mtDNA variant m.3243A>G, the most common cause of adult mitochondrial disease. We found that these individuals may have an elevated risk […]
Haplotype studies and the use of a nearby tagging variant confirm a founder origin for an intragenic CYP11B1 inversion (Contributed by Dr. Alistair T Pagnamenta)
Genomic inversions occur when a stretch of DNA flips over, reversing its orientation. The absence of copy-number change can make these variants hard to spot. In this commentary, Pagnamenta and colleagues examine an inversion recently reported by Janot et al. in a gene linked to disorders of sexual development. They show it can be detected […]
Analysis of familial exudative vitreoretinopathy (FEVR) cases in the UK 100 000 genomes project increases diagnostic rate and implicates heterozygous CTNND1 mutations in FEVR (Contributed by Dr. Dong Sun)
Familial exudative vitreoretinopathy (FEVR) is a blinding disorder caused by abnormal development of retinal blood vessels. This study reanalyses whole genome sequence data from 59 individuals with FEVR in the UK 100,000 Genomes Project (100KGP). Bespoke analysis led to molecular diagnoses in 39%, almost doubling the diagnostic success of standard analyses. New cases solved include […]