People with a tumor predisposition syndrome have increased risks of various tumors. The cause is an inherited mutation in a certain gene, usually detected with a DNA-test using blood. Sometimes a novel mutation develops during early embryonic development. The mutation is then not present in all cells, which is called mosaicism. In mosaicism, a blood test […]
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Mosaic variegated aneuploidy as a novel feature in patients with Mulibrey nanism and TRIM37 variants
This study reveals new information on the disease mechanisms of a hereditary condition called Mulibrey nanism. Mulibrey nanism occurs if a child inherits a genetic change in a gene called TRIM37 from both parents (recessive inheritance). Children and adults with Mulibrey nanism are shorter than average, they may develop a rare type of heart disease, […]
Reasoning Based AI in Rare Disease Diagnosis
A recent study in Nature marks a conceptual advance in medical genetics by reframing rare disease diagnosis as a coordinated reasoning task rather than a static prediction problem. The proposed agentic system orchestrates phenotype, genotype, and knowledge retrieval modules under a large language model host, generating ranked hypotheses with transparent, evidence linked logic. It is […]
Toward calibrated variant effect estimates
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 fetal structural anomalies and adult disease risk, (2) expand and refine genotype-phenotype relationships for rare neurodevelopmental and syndromic conditions, and […]
Reclassification of variants of uncertain significance in type 1 collagen genes: a national reference laboratory experience.
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
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
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
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
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
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 […]