David Fitzpatrick
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View article: <i>KMT2B</i>-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.
<i>KMT2B</i>-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Open
Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caud…
View article: Whole Genome Sequencing of “Mutation‐Negative” Individuals With Cornelia de Lange Syndrome
Whole Genome Sequencing of “Mutation‐Negative” Individuals With Cornelia de Lange Syndrome Open
This study was aimed at assessing the diagnostic utility of whole genome sequence analysis in a well‐characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic…
View article: Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants
Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants Open
Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combi…
View article: Single-cell analyses reveal transient retinal progenitor cells in the ciliary margin of developing human retina
Single-cell analyses reveal transient retinal progenitor cells in the ciliary margin of developing human retina Open
View article: Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features
Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features Open
Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the s…
View article: A human embryonic limb cell atlas resolved in space and time
A human embryonic limb cell atlas resolved in space and time Open
View article: Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia
Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia Open
Background Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic an…
View article: Heterozygous loss-of-function<i>SMC3</i>variants are associated with variable and incompletely penetrant growth and developmental features
Heterozygous loss-of-function<i>SMC3</i>variants are associated with variable and incompletely penetrant growth and developmental features Open
Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the s…
View article: Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants
Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants Open
Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combi…
View article: Spatiotemporal single cell analyses reveal a transient population of retinal progenitor cells in the ciliary margin of developing human retina
Spatiotemporal single cell analyses reveal a transient population of retinal progenitor cells in the ciliary margin of developing human retina Open
The emergence of retinal progenitor cells (RPCs) and differentiation to various retinal cell types represent fundamental processes during retinal development. Herein, we provide a comprehensive single cell characterisation of transcription…
View article: Characterization of an eye field-like state during optic vesicle organoid development
Characterization of an eye field-like state during optic vesicle organoid development Open
Specification of the eye field (EF) within the neural plate marks the earliest detectable stage of eye development. Experimental evidence, primarily from non-mammalian model systems, indicates that the stable formation of this group of cel…
View article: Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland Open
Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Ch…
View article: EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders
EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders Open
Background Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools to improve precision while ensuring high recall are critical to successful mainstream clinical genomic …
View article: P451: The Gene Curation Coalition works to resolve discrepancies in gene-disease validity assertions
P451: The Gene Curation Coalition works to resolve discrepancies in gene-disease validity assertions Open
View article: Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study
Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study Open
View article: Clustered variants in the 5′ coding region of TRA2B cause a distinctive neurodevelopmental syndrome
Clustered variants in the 5′ coding region of TRA2B cause a distinctive neurodevelopmental syndrome Open
Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the o…
View article: Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing
Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing Open
View article: IMPROVE-DD: Integrating multiple phenotype resources optimizes variant evaluation in genetically determined developmental disorders
IMPROVE-DD: Integrating multiple phenotype resources optimizes variant evaluation in genetically determined developmental disorders Open
Diagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multiple Phenot…
View article: Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia
Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia Open
Classical aniridia is a congenital and progressive panocular disorder almost exclusively caused by heterozygous loss-of-function variants at the PAX6 locus. We report nine individuals from five families with severe aniridia and/or micropht…
View article: Robust Genetic Analysis of the X-Linked Anophthalmic (Ie) Mouse
Robust Genetic Analysis of the X-Linked Anophthalmic (Ie) Mouse Open
Anophthalmia (missing eye) describes a failure of early embryonic ocular development. Mutations in a relatively small set of genes account for 75% of bilateral anophthalmia cases, yet 25% of families currently are left without a molecular …
View article: Author Correction: Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data
Author Correction: Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data Open
View article: Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome
Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome Open
Aims This study assesses the diagnostic utility of whole genome sequence analysis in a well-characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic testing …
View article: Characterization of an Eye Field-like State during Optic Vesicle Organoid Development
Characterization of an Eye Field-like State during Optic Vesicle Organoid Development Open
Specification of the eye field (EF) within the neural plate marks the earliest detectable stage of eye development. Experimental evidence, primarily from non-mammalian model systems, indicates that the stable formation of this group of cel…
View article: Robust genetic analysis of the X-linked anophthalmic (<i>Ie</i>) mouse
Robust genetic analysis of the X-linked anophthalmic (<i>Ie</i>) mouse Open
Anophthalmia (missing eye) describes a failure of early embryonic ocular development. Mutations in a relatively small set of genes account for 75% of bilateral anophthalmia cases, yet 25% of families currently are left without a molecular …
View article: Optimising diagnostic yield in highly penetrant genomic disease
Optimising diagnostic yield in highly penetrant genomic disease Open
Background Pediatric disorders include a range of highly genetically heterogeneous conditions that are amenable to genome-wide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. Met…
View article: Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Recommendations for clinical interpretation of variants found in non-coding regions of the genome Open
View article: IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders
IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders Open
Summary Diagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multipl…
View article: The Gene Curation Coalition: A global effort to harmonize gene–disease evidence resources
The Gene Curation Coalition: A global effort to harmonize gene–disease evidence resources Open
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 an…
View article: A human embryonic limb cell atlas resolved in space and time
A human embryonic limb cell atlas resolved in space and time Open
Human limbs emerge during the fourth post-conception week as mesenchymal buds which develop into fully-formed limbs over the subsequent months. Limb development is orchestrated by numerous temporally and spatially restricted gene expressio…
View article: Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study
Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study Open
Purpose Structural mosaicism has been previously implicated in developmental disorders. We aim to identify rare mosaic chromosomal alterations (MCAs) in probands with severe undiagnosed developmental disorders. Methods We identified MCAs i…