Alistair T. Pagnamenta
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View article: Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia
Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia Open
View article: Reduced penetrance of <i>COL1A1/2</i> pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort
Reduced penetrance of <i>COL1A1/2</i> pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort Open
Osteogenesis imperfecta (OI) is under consideration for inclusion in several genomic newborn screening initiatives, but its penetrance in clinically-unselected populations is currently unknown. It is an exemplar condition for evaluating pe…
View article: Empathy in mild cognitive impairment: a preliminary clinical comparative study in Southern Switzerland using the interpersonal reactivity index (IRI) and the story-based empathy task (SET)
Empathy in mild cognitive impairment: a preliminary clinical comparative study in Southern Switzerland using the interpersonal reactivity index (IRI) and the story-based empathy task (SET) Open
Introduction Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and dementia, frequently associated with subtle deficits in social cognition. Empathy, a core component of social cognition, encompasses both affecti…
View article: Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project
Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project Open
Background Whole-genome sequencing (WGS) projects for rare disease diagnosis typically yield a diagnostic rate of approximately 25-40%, dependent particularly on patient selection and the extent of prior genetic testing. The Scottish Genom…
View article: Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome
Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome Open
Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing…
View article: Machine learning ascertains candidate genes for rare musculoskeletal disorders in 100,000 Genomes Project
Machine learning ascertains candidate genes for rare musculoskeletal disorders in 100,000 Genomes Project Open
View article: Biallelic <scp><i>FGF4</i></scp> Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency
Biallelic <span><i>FGF4</i></span> Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency Open
The thoracic dystrophies are inherited skeletal conditions where abnormal embryonic development of the thoracic skeleton results in a narrow chest, pulmonary hypoplasia, and respiratory insufficiency, which can be severe or lethal. The maj…
View article: Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome
Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome Open
Purpose To quantify the impact of non-canonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and Familial Thoracic Aortic Aneurysm Disease (FTAAD). Meth…
View article: A Cryptic <scp> <i>CBFB</i> </scp> Deletion–Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia
A Cryptic <span> <i>CBFB</i> </span> Deletion–Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia Open
CBFB encodes the core‐binding factor β subunit, a small protein which heterodimerises with RUNX1‐3 and activates transcription of genes important in bone development. Recently, five families with cleidocranial dysplasia (CCD) were identifi…
View article: Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy
Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy Open
View article: Clinical and genetic characterization of a progressive <i>RBL2</i>-associated neurodevelopmental disorder
Clinical and genetic characterization of a progressive <i>RBL2</i>-associated neurodevelopmental disorder Open
Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. H…
View article: Hiding in plain sight: a partial deletion of <i>BRCA1</i> exon 7 undetectable by MLPA is a Nepali founder variant
Hiding in plain sight: a partial deletion of <i>BRCA1</i> exon 7 undetectable by MLPA is a Nepali founder variant Open
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provide…
View article: Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus
Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus Open
The aim of this work was to identify the underlying genetic cause in a four-generation family segregating an unusual phenotype comprising a severe form of skeletal Class II malocclusion with gingival hyperplasia. SNP array identified a cop…
View article: An autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, is caused by the<i>de novo</i>creation of a cardiomyocyte enhancer
An autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, is caused by the<i>de novo</i>creation of a cardiomyocyte enhancer Open
A substantial proportion of mutations underlying rare Mendelian diseases remain unknown, potentially because they lie in the non-coding genome. Here, we report the mapping of the causal mutation of an autosomal dominant cardiac arrhythmia …
View article: The impact of inversions across 33,924 families with rare disease from a national genome sequencing project
The impact of inversions across 33,924 families with rare disease from a national genome sequencing project Open
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 familie…
View article: <i>Ide</i>copy number variant does not influence lesion size and mortality in two C57BL/6J mouse models of cerebrovascular ischemia nor in human cerebrovascular disease. An exploratory study
<i>Ide</i>copy number variant does not influence lesion size and mortality in two C57BL/6J mouse models of cerebrovascular ischemia nor in human cerebrovascular disease. An exploratory study Open
Contrary to the common belief, the most commonly used laboratory mouse inbred strains are shaped by a distinctive genetic and phenotypic diversity. In the past 10 years next generation sequencing unveiled a wide spectrum of genetic variant…
View article: A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3
A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3 Open
View article: Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder
Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder Open
Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. H…
View article: <i>RTN2</i> deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity
<i>RTN2</i> deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity Open
Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 r…
View article: A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3
A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3 Open
View article: Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications Open
View article: <i>FILIP1</i>-associated neuromuscular disorder and phenotypic blending due to paternal UPD6
<i>FILIP1</i>-associated neuromuscular disorder and phenotypic blending due to paternal UPD6 Open
View article: Autosomal recessive <i>VWA1</i>-related disorder: comprehensive analysis of phenotypic variability and genetic mutations
Autosomal recessive <i>VWA1</i>-related disorder: comprehensive analysis of phenotypic variability and genetic mutations Open
A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (V…
View article: Biallelic <i>NUDT2</i> variants defective in mRNA decapping cause a neurodevelopmental disease
Biallelic <i>NUDT2</i> variants defective in mRNA decapping cause a neurodevelopmental disease Open
Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and…
View article: Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data
Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data Open
To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited …
View article: Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases
Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases Open
View article: CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology Open
View article: Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project
Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project Open
Background Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Proje…
View article: Pure cerebellar ataxia due to bi‐allelic PRDX3 variants including recurring p.Asp202Asn
Pure cerebellar ataxia due to bi‐allelic PRDX3 variants including recurring p.Asp202Asn Open
Bi‐allelic variants in peroxiredoxin 3 ( PRDX3 ) have only recently been associated with autosomal recessive spinocerebellar ataxia characterized by early onset slowly progressive cerebellar ataxia, variably associated with hyperkinetic an…
View article: Genome sequencing identifies <i>KMT2E</i> ‐disrupting cryptic structural variant in a female with O'Donnell‐Luria‐Rodan syndrome
Genome sequencing identifies <i>KMT2E</i> ‐disrupting cryptic structural variant in a female with O'Donnell‐Luria‐Rodan syndrome Open
We describe a patient from the 100,000 Genomes Project with a complex de novo structural variant within KMT2E leading to O'Donnell-Luria-Rodan syndrome. This case expands the mutational spectrum for this syndrome and highlights the importa…