Categoría: JMG First
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Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study
BackgroundClassification of heterozygous germline PTEN variants in patients with, or suspected of having, PTEN hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveill…
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Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature
BackgroundDysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours…
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Hypertrophic cardiomyopathy: a genome-wide association meta-analysis and polygenic risk score
BackgroundHypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence,…
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Exome sequencing and large-scale analysis of electronic medical record-linked biobank data identify candidate deafness genes
IntroductionRapid advances in whole-exome sequencing (WES) have enabled large-scale detection of pathogenic variants. Although hundreds of genes are implicated in hearing loss, up to half of inherited cases remain unsolved, limiting eligibility for gen…
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Exploring the clinical and mutational spectrum of MORC2-associated disorders
BackgroundPathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuro…
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Rapid minigene workflow for functional reclassification of splicing variants in hereditary cancer diagnostics
BackgroundNext-generation sequencing of cancer predisposition genes is routinely used in hereditary cancer diagnostics. However, a substantial fraction of detected variants remains clinically unresolved. Using a customised 77-gene panel, we analysed 21…
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Risk of breast cancer after ovarian cancer in germline BRCA1/2 heterozygotes
Breast cancer risk after ovarian cancer in germline BRCA1/2 heterozygotes remains uncertain, with a recent large multicentre international study reporting lower-than-expected incidence in the first decade after ovarian cancer diagnosis (Apostol et al. …
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Founder variant in OTOG causing non-syndromic sensorineural hearing loss in Irish traveller population
Deafness is a common multifactorial sensory disorder with numerous underlying causes (genetic, environmental) and a broad range of impact on humans. To date, 156 non-syndromic hearing loss-associated genes have been identified (DFN) and 75%–80% f…
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Childhood-onset neurodegeneration and brain atrophy: defining UBTF-related developmental regression and progressive ataxia
BackgroundThe heterozygous variant c.628G>A (p.Glu210Lys) in UBTF (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed developme…
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Childhood-onset neurodegeneration and brain atrophy: defining UBTF-related developmental regression and progressive ataxia
BackgroundThe heterozygous variant c.628G>A (p.Glu210Lys) in UBTF (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed developme…