Moyra Smith

• University of California, Irvine

Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with...

Patients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based metho...

Patients with tuberous sclerosis complex (TSC) develop an array of multi-organ disease manifestations, with angiomyolipomas (AML) and cysts in the kidneys being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital in lowering TSC patient morbidity and mortality. However, current standard of care for imagi...

Recent advances in neuroscience and genetics have greatly expanded our understanding of the brain and of the etiological factors involved in developmental delay and mental retardation. At the same time, the human genome project has yielded a wealth of information on DNA sequencing, regulation of gene expression, epigenetics, and functional aspects...

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated...

This chapter presents examples of the application of genomic analyses and sequence analyses in determination of underlying causes of genetic disorders. There is a particular emphasis on developmental disorders and neurological disorders. The chapter also includes information on imprinting and on disorders associated with imprinting changes. Applica...

Database resources established to document information on phenotypic features of genetic diseases are presented in this chapter. Also considered and documented are aspects of genetic heterogeneity where highly similar phenotypic features are caused by abnormalities in different genes and phenotypic variability where individuals with the same geneti...

In reviewing early studies on specific proteins that have maintained clinical importance even until the present it seems particularly relevant to consider the ABO and Rh blood group systems. The chapter starts with landmark discovery of AB blood group antigens by Landsteiner in 1901 and progresses through discoveries of other blood groups especiall...

In this chapter, public health and clinical applications of genetic and genomic discoveries are reviewed. Specific programs reviewed include newborn screening programs in several countries. The chapter also includes information on the population distribution of several genetic disorders that should be considered during diagnosis and patient care.

Advances in analyses of genes, their products, and their functions, and identification of disease-related alterations in the latter, have paved the way to design of specific therapies. Specific therapies reviewed in this chapter include those directed at specific proteins and enzymes, those that utilize small molecules to act as chaperones and ther...

The purpose of this chapter is to document progress in analysis of several genetic disorders starting in the late 19th century on to illustrate importance of careful clinical evaluations along with family studies. Progress in delineation of the underlying genetic and genomic defects in several core genetic disorders is presented.

In this chapter genomic structural changes, genes, and mutations associated with pediatric and adult cancers are presented. Both germline and somatic mutations are considered. Data on solid tumors and hematologic cancers are presented. In addition, information is presented on advances in molecular detection of cancer. Data on advances in cancer the...

Improved analyses of the regulatory genome have important clinical implications for both common and rare diseases. Studies on specific disorders and laboratory saturation mutation analyses have revealed that disruptions in regulatory elements can lead to major functional disruptions and diseases. The regulatory genome can be disrupted by nucleotide...

In this chapter genetic factors that influence pharmacokinetics and pharmacodynamics are presented. Genetic polymorphisms in the CYP450 system are discussed. Aberrant responses to medications in individuals with specific genetic diseases including porphyria and G6PD deficiency are presented. Aspects of therapy developments and translation of biomed...

Clearly, progress between 1920 and 1970 was built on earlier efforts and achievements in the 19th century and in the early years of the 20th century. Key findings in early biochemistry were reviewed by Teich and Needham in 1992. Studies on proteins and earlier methods of separations of different proteins were achieved. In 1948, Tiselius received a...

Studies in personalized medicine are based on the concept that in individual patients diagnosed with the same disease there are frequently different underlying causative factors. These can include different genetic and genomic factors. Based on these differences different patients may therefore respond differently to therapy. In this chapter differ...

This chapter explores early history of discovery of units of inheritance and includes information from works of Mendel, Boveri, Janssens, and Bateson. Studies of Morgan and Sutton on the chromosomal basis of inheritance are also included. Later key developments discussed include studies on DNA and its structure and sequence. Discovery of chromosome...

Gene therapy approaches discussed in this chapter include strategies to block gene mutations and strategies to add normal genes in cases where a specific gene is dysfunctional. Also included is information on newer techniques to edit gene mutations using CRSPR-Cas9 approaches and discussion of base editing and prime editing. Specific genetic condit...

This chapter presents development of techniques for DNA sequencing of the human genome and human gene analyses. Sequencing techniques discussed include Sanger sequencing, second generation sequencing, and long-read sequencing. Aspects of gene mapping relative to human chromosomes are presented. Applications of sequencing to studies of human disease...

Individuals with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDDs) often carry disruptive mutations in genes that are depleted of functional variation in the broader population. We build upon this observation and exome sequencing from 154,842 individuals to explore the allelic diversity of rare protein-coding variation c...

Background The nucleotide binding protein-like ( NUBPL ) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different fr...

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...

https://www.sciencedirect.com/book/9780128196137/gene-environment-interactions

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...

We present the largest exome sequencing study to date focused on rare variation in autism spectrum disorder (ASD) (n=35,584). Integrating de novo and case-control variation with an enhanced Bayesian framework incorporating evolutionary constraint against mutation, we implicate 99 genes in ASD risk at a false discovery rate (FDR) ≤ 0.1. Of these 99...

Definitive molecular diagnoses in disorders apparently due to genetic or genomic defects are still lacking in a significant number of investigated cases, despite use of studies designed to discover defects in the protein coding regions of the genome. Increasingly studies are being designed to search for defects in the non-protein coding genome, and...

Autosomal Dominant Optic Atrophy (ADOA) is a neuro-ophthalmic disease characterized by progressive bilateral vision loss, pallor of the optic disc, central vision loss, and impairment of color vision. Additionally, a small percentage of patients experience hearing loss and ataxia, while recent studies suggest disruption of cardiac and neuromuscular...

Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of mic...

The chapters in the second edition of David Latchman’s text on Gene Control delineate the structures, molecular components and processes required to control gene expression. Taken together, the chapters provide an outstanding, up-to-date review of modern molecular genetics and functional genomics.

The aim and scope of this book is to review current information on human development and processes of differentiation that have benefited from breakthrough analyses in stem cell biology, elucidation of genome and gene architecture and aspects of regulation of gene expression, analysis of signaling systems and transcription factor actions. Insights...

This chapter focuses on evidence for increased nuclear genome instability in autism. Duplication and deletions of specific chromosome segments leading to altered gene dosage (copy number variants CNVs) are common in autism. Additional evidence for genomic instability is the higher frequency of nucleotide mutation in nuclear DNA in autistic probands...

To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNV...

The goal of this resource is to present steps in the pathways of exploration to connect genotype to phenotype and to consider how alterations in genomes impact disease. Topics reviewed include investigations in genome architecture, gene structure, gene regulation epigenetic modifications and function of organelles including mitochondria, and the en...

The breadth and scope of new information makes difficult a selection of topics to be included in a limited review of highlights of the year. Admittedly, the choices are idiosyncratic. The eight topics presented here are (1) structural and copy number variants in the human genome; (2) progress in defining genetic factors in the etiology of schizophr...

In this review we will evaluate evidence that altered gene dosage and structure impacts neurodevelopment and neural connectivity through deleterious effects on synaptic structure and function, and evidence that the latter are key contributors to the risk for autism. We will review information on alterations of structure of mitochondrial DNA and abn...

In this new book, noted geneticist and veteran OUP author, Moyra Smith, will present a comprehensive critical review of the translation of genetic and genomic research into health care. Dr. Smith’s motivation for writing is driven by the gap that exists between the rather amazing discoveries in medical genetics and genomics at basic science levels...

In this new book, noted geneticist and veteran OUP author, Moyra Smith, will present a comprehensive critical review of the translation of genetic and genomic research into health care. Dr. Smith’s motivation for writing is driven by the gap that exists between the rather amazing discoveries in medical genetics and genomics at basic science levels...

In this new book, noted geneticist and veteran OUP author, Moyra Smith, will present a comprehensive critical review of the translation of genetic and genomic research into health care. Dr. Smith’s motivation for writing is driven by the gap that exists between the rather amazing discoveries in medical genetics and genomics at basic science levels...

In this new book, noted geneticist and veteran OUP author, Moyra Smith, will present a comprehensive critical review of the translation of genetic and genomic research into health care. Dr. Smith’s motivation for writing is driven by the gap that exists between the rather amazing discoveries in medical genetics and genomics at basic science levels...

In this new book, noted geneticist and veteran OUP author, Moyra Smith, will present a comprehensive critical review of the translation of genetic and genomic research into health care. Dr. Smith’s motivation for writing is driven by the gap that exists between the rather amazing discoveries in medical genetics and genomics at basic science levels...

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected...

Tuberous sclerosis (TSC) is a multisystem autosomal dominant hamartosis whose genetics is complicated by reduced penetrance and widely varying clinical expression. Results of linkage analyses have variously suggested two different locations for a TSC gene. A collaborative dataset has been assembled to clarify the issue of genetic heterogeneity. We...

We performed a genome-wide linkage scan using highly polymorphic microsatellite markers. To minimize genetic heterogeneity, we focused on sibpairs meeting the strict diagnosis of autism. In our primary analyses, we observed a strong linkage signal (P=0.0006, 133.16 cM) on chromosome 7q at a location coincident with other linkage studies. When a mor...