ORCID Profile
0000-0003-4861-969X
Current Organisations
The University of Edinburgh
,
MRC Human Genetics Unit
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Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NG.3627
Publisher: eLife Sciences Publications, Ltd
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1038/S41598-017-03054-8
Abstract: Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS , which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1 , BBS9 , GNAS , MKKS , CLOCK and ANGPTL6 . The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 −3 ), highlighting the challenges of testing rare variant associations and the need for very large s le sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1038/NATURE21062
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2021
DOI: 10.1101/2021.12.28.21267792
Abstract: The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight ex les of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants. These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-12-2018
Abstract: The genetics of developmental disorders (DDs) is complex. Martin et al. wanted to determine the degree of recessive inheritance of DDs in protein-coding genes. They examined the exomes of more than 6000 families in populations with high and low proportions of consanguineous marriages. They found that 3.6% of DDs in in iduals of European ancestry involved recessive coding disorders, less than a tenth of the levels previously estimated. Furthermore, among South Asians with high parental relatedness, rather than most of the disorders arising from inherited variants, fewer than half had a recessive coding diagnosis. Science , this issue p. 1161
Publisher: Public Library of Science (PLoS)
Date: 24-04-2014
Publisher: Springer Science and Business Media LLC
Date: 06-03-2015
DOI: 10.1038/NCOMMS6681
Abstract: Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project ( N =2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 ( N =16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P =6.15 × 10 −9 ) and a new independent variant in PDE8B (MAF=10.4%, P =5.94 × 10 −14 ). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P =1.27 × 10 −9 ) tagging a rare TTR variant (MAF=0.4%, P =2.14 × 10 −11 ). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF %) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.
Publisher: BMJ
Date: 14-08-2014
Publisher: Springer Science and Business Media LLC
Date: 05-10-2015
DOI: 10.1038/NG.3410
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NATURE14962
Publisher: Cold Spring Harbor Laboratory
Date: 23-03-2020
DOI: 10.1101/2020.03.18.20037960
Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders (DDs), and X-linked causes have been hypothesised to underlie the higher DD rates in males. We evaluated the burden of X-linked coding variation in 11,046 DD patients, and found a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We developed an improved strategy to detect novel X-linked DDs and identified 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known DD-associated genes. Importantly, we estimated that, in male probands, only 13% of inherited rare missense variants in known DD-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for in idual X-linked disorders.
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1086/302492
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0955-2235(90)90002-2
Abstract: Type beta transforming growth factors (TGF beta s) are members of a large superfamily of related proteins, each of which plays a pivotal role in embryonic processes. The TGF beta s per se are at least five in number, though only three isoforms have been identified in mammals. Here we will review the evidence, taken from in vitro studies on bioactivity and histochemical localization of RNAs and encoded proteins in vivo, that TGF beta 1, beta 2 and beta 3 are involved in several mammalian developmental processes, including control of growth, differentiation, tissue inductions and morphogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 02-10-2020
DOI: 10.1101/2020.10.02.20194241
Abstract: Structural Variation (SV) describes a broad class of genetic variation greater than 50bps in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DD). Patients presenting with DD are often referred for diagnostic testing with chromosomal microarrays (CMA) to identify large copy-number variants (CNVs) and/or with single gene, gene-panel, or exome sequencing (ES) to identify single nucleotide variants, small insertions/deletions, and CNVs. However, patients with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the novel tool ‘InDelible’, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 64 rare, damaging variants in genes previously associated with DD missed by standard SNV, InDel or CNV discovery approaches. Clinical review of these 64 variants determined that about half (30/64) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.3%. Of particular interest were seven confirmed de novo variants in MECP2 which represent 35.0% of all de novo protein truncating variants in MECP2 among DDD patients. InDelible provides a framework for the discovery of pathogenic SVs that are likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 11-2017
Publisher: Hindawi Limited
Date: 29-08-2003
DOI: 10.1002/HUMU.10264
Publisher: Springer Science and Business Media LLC
Date: 05-06-2015
DOI: 10.1038/NCOMMS8074
Abstract: The analysis of in iduals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas , accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Publisher: Springer Science and Business Media LLC
Date: 09-1986
DOI: 10.1007/BF01314296
Abstract: In 2006, a novel gammaretrovirus, XMRV (xenotropic murine leukemia virus-related virus), was discovered in some prostate tumors. A more recent study indicated that this infectious retrovirus can be detected in 67% of patients suffering from chronic fatigue syndrome (CFS), but only very few healthy controls (4%). However, several groups have published to date that they could not identify XMRV RNA or DNA sequences in other cohorts of CFS patients, while another group detected murine leukemia virus (MLV)-like sequences in 87% of such patients, but only 7% of healthy controls. Since there is a high degree of similarity between XMRV and abundant endogenous MLV proviruses, it is important to distinguish contaminating mouse sequences from true infections. DNA from the peripheral blood of 112 CFS patients and 36 healthy controls was tested for XMRV with two different PCR assays. A TaqMan qPCR assay specific for XMRV pol sequences was able to detect viral DNA from 2 XMRV-infected cells (~ 10-12 pg DNA) in up to 5 μg of human genomic DNA, but yielded negative results in the test of 600 ng genomic DNA from 100,000 peripheral blood cells of all s les tested. However, positive results were obtained with some of these s les, using a less specific nested PCR assay for a different XMRV sequence. DNA sequencing of the PCR products revealed a wide variety of virus-related sequences, some identical to those found in prostate cancer and CFS patients, others more closely related to known endogenous MLVs. However, all s les that tested positive for XMRV and/or MLV DNA were also positive for the highly abundant intracisternal A-type particle (IAP) long terminal repeat and most were positive for murine mitochondrial cytochrome oxidase sequences. No contamination was observed in any of the negative control s les, containing those with no DNA template, which were included in each assay. Mouse cells contain upwards of 100 copies each of endogenous MLV DNA. Even much less than one cell's worth of DNA can yield a detectable product using highly sensitive PCR technology. It is, therefore, vital that contamination by mouse DNA be monitored with adequately sensitive assays in all s les tested.
Publisher: Cold Spring Harbor Laboratory
Date: 03-01-2025
DOI: 10.1101/2022.01.03.21268593
Abstract: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. The GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. Based on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 03-02-2013
DOI: 10.1038/NG.2552
Abstract: One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in in iduals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated in iduals with familial multiple spinal meningiomas without NF2 mutations. We identified two in iduals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further in iduals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from in iduals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology.
Publisher: Wiley
Date: 11-1984
DOI: 10.1111/J.1751-0813.1984.TB07152.X
Abstract: Representative strains of EHV isolated from an aborted foetus and from a horse with rhinopneumonitis in New Zealand had restriction endonuclease DNA fingerprints typical of those usually associated with these syndromes elsewhere and now designated EHV1 and 4 respectively. EHV1 was isolated from the brain and spinal cord of a 4-year-old gelding that died of myeloencephalitis. A mare on the same farm, at about the same time as the gelding developed myeloencephalitis, aborted and EHV1 was isolated from the tissues of the aborted foetus. Restriction endonuclease DNA fingerprints of the viruses isolated from myeloencephalitis and abortion were indistinguishable by Bam HI but were distinguishable using Bgl I, Pvu II, Xho I and Hind III. The restriction endonuclease DNA fingerprints of 3 EHV1 strains known to cause myeloencephalitis were compared with each other and with EHV1 strains not known to be associated with myeloencephalitis. The Bgl I Pvu II and Hind III DNA fingerprints of the 3 myeloencephalogenic strains appear distinguishable from non-myeloencephalogenic strains. Abortion was induced in a mare by intrauterine inoculation of EHV4. The Bam HI, Bgl I, Pvu II, Xho I and Hind III restriction endonuclease DNA fingerprints of the inoculum virus were indistinguishable from virus recovered from the foetus. It was concluded that passage of the virus through the foetus did not detectably alter the restriction endonuclease DNA fingerprint.
Publisher: Springer Science and Business Media LLC
Date: 24-12-2014
DOI: 10.1038/NATURE14135
Publisher: Springer Science and Business Media LLC
Date: 09-01-2017
DOI: 10.1038/NG.3743
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for David R. FitzPatrick.