Victoria Siu - Academia.edu (original) (raw)

Papers by Victoria Siu

American Journal of Medical Genetics Part A, 2020

The 40th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred August 23rd ‐... more The 40th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred August 23rd ‐28th, 2019 at the Snowbird Resort in Snowbird, Utah. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis from around the world. In addition to mechanisms of morphogenesis and delineation of new syndromes, the Workshop highlighted five themes: deformations, disruptions and fetal dysmorphology; orofacial clefting; central nervous system malformations; ciliopathies; and X‐linked intellectual disabilities. This Conference Report includes the abstracts presented at the 2019 Workshop.

Human Genetics and Genomics Advances, 2021

Summary Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associ... more Summary Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, Mar 1, 2018

Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal... more Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection...

Brain

In the field of rare diseases, progress in molecular diagnostics led to the recognition that vari... more In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0–24 years). Most individuals prese...

uwomeds.com

... Recently, well-known Harvard professor and bestselling author of The Stuff of Thought, Steven... more ... Recently, well-known Harvard professor and bestselling author of The Stuff of Thought, StevenPinker, allowed his entire genome not only to ... would say a genetic Miranda warning.2,13 This third strategy involves physicians informing their patients of the circumstances under ...

Research article Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 a... more Research article Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions

Genetics in Medicine, 2022

Journal of Obstetrics and Gynaecology Canada

Journal of Obstetrics and Gynaecology Canada, 2022

A 35-year-old was referred to genetics for two soft markers but also found to have polyhydramnios... more A 35-year-old was referred to genetics for two soft markers but also found to have polyhydramnios. The couple were Old Order Mennonite and carrier testing allowed for targeted investigation of syndromes associated with polyhydramnios in this population. Both parents were carriers of a 7304bp deletion in the STRADA (LYK5) gene causing an autosomal recessive syndrome of polyhydramnios, megalencephaly and symptomatic epilepsy. This led to early recognition and treatment of neonatal seizures. Targeted testing can significantly shorten the diagnostic odyssey and decrease costs of investigations, an especially important consideration for families who do not accept health insurance.

Genetics in medicine : official journal of the American College of Medical Genetics, Jan 19, 2016

The purpose of the current study was to assess the penetrance of NRXN1 deletions. We compared the... more The purpose of the current study was to assess the penetrance of NRXN1 deletions. We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3' end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5' NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls...

Journal of Medical Genetics, 2001

The American Journal of Human Genetics, 2012

International Journal of Molecular Sciences, 2021

A growing number of genetic neurodevelopmental disorders are known to be associated with unique g... more A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding o...

This case report describes a young boy with concomitant genetically-confirmed Duchenne muscular d... more This case report describes a young boy with concomitant genetically-confirmed Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy with a novel dystrophin mutation in exon 6 and a D4Z4 fragment of 31 kb. This child presented with a more severe phenotype than expected for either individual disease process and underscores the role for thorough diagnostic investigation in identifying atypical clinical presentations. 2008 Published by Elsevier B.V.

The Journal of Pediatrics, 2013

To determine the incidence and neonatal morbidity and mortality of congenital myotonic dystrophy ... more To determine the incidence and neonatal morbidity and mortality of congenital myotonic dystrophy (CDM) in Canada. The study has 2 phases. A 5-year prospective monthly surveillance of incident cases of CDM conducted via the Canadian Pediatric Surveillance Program, from March 1, 2005-February 28, 2010, and a 5-year cohort study of eligible incident cases, which is ongoing and not the subject of this report. A total of 121 cases were reported, with 38 confirmed as CDM. The incidence of CDM in Canada is 2.1/100,000 (1/47,619) live births. The cases were reported from 8 provinces and 1 territory. The highest reported incidence was Ontario with 15, followed by British Columbia with 7, and Quebec with 6. External validation of cases was performed. The trinucleotide repeat level varied from 550-3100. Twenty-two (58%) of the children were the index cases for their families. Seventeen children are currently enrolled in the ongoing cohort study. Surveillance and prospective examination of CDM at a population level is important, as the impact of this rare disease is systemic, chronic, and associated with significant morbidity and mortality throughout childhood.

Genetics in Medicine, 2020

Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individua... more Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were commo...