DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation

Very few families with mutations in DDX58 (RIG-I), an innate immune sensor, have been described with a multisystem disorder featuring blood vessel calcium deposition, a skin rash, and childhood glaucoma. Here, we have identified two unrelated families that share a rare variant in DDX58, and showed that it causes disease by a gain-of-function mechanism and tissue specific effects.  […]

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Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease

Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene (GLA) leading to enzymatic deficiency of α-galactosidase A and ultimately in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (Lyso-Gb3). The major metabolite of FD plasma Lyso-Gb3 appears as a potential marker of disease […]

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Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

To find new genes that cause congenital diaphragmatic hernia (CDH)—a severe life-threatening birth defect—we used previously published data generated using a machine learning algorithm that compared all genes in the genome to a small set of known CDH genes. By comparing patterns using the machine learning algorithm data, and using information from a clinical database […]

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Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders

As babies develop, their skull needs to get bigger to give the developing brain enough space to grow. We study craniosynostosis, a serious condition (affecting ~1/2,000 children) that occurs when one or more gaps between the skull bones (cranial sutures) fuses too early. Here, we used high throughput DNA sequencing technologies in more than 1,600 […]

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Calibration of polygenic risk scores is required prior to clinical implementation: results of three common cancers in UKB

Studies have shown a consistent trend between polygenic risk score percentiles and disease risk in populations, and this evidence is used to support its clinical use. However, in clinic, polygenic risk score values, not percentiles, are used for estimating disease lifetime risk. In this study, we assessed the calibration of polygenic risk score values for […]

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Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay

We present a child with an unexpected combination of both Beckwith-Wiedemann syndrome (BWS), an imprinted overgrowth condition, and IMAGe syndrome, a growth-restricted condition. The child also has developmental delay and microcephaly, apparently unrelated features. However, all features can potentially be explained by a single CDKN1C delins mutation, de novo mosaic in the maternal grandfather, due […]

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Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy

Nephronophthisis-related ciliopathies (NPH-RC) are important genetically disorders causing chronic renal failure (CRF) in children and adolescents.This group of diseases involved multiple pathogenic genes and organs.We firstly studied the genotype and phenotype spectra in a largest China cohort of NPHP-RC based on national register network (www.ccgkdd.com.cn). NPHP1 and NPHP3 are the most common pathogenic genes, and […]

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Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region

Over 2,400 years ago, Hippocrates noticed that eye misalignment, or strabismus, tended to cluster in families. This observation represents an early recognition of what we now recognize as genetic causes. However, genetic causes of isolated strabismus, which occur in the absence of other symptoms, remain elusive.   In a large family, we identify a piece […]

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Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations

Standardization of practice in classification of variants in cancer susceptibility genes has improved substantially since UK adoption of the 2015 American College of Medical Genetics (ACMG) framework. However, considerable inconsistency between laboratories persists, largely around how evidence items are weighted and combined. We present consensus recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK), our national […]

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