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At least 19 recordsLinked to original sources
PubMed1976

The diagnosis of genetic disorders before birth.

Genetic disorders account for a significant number of the health care problems in our society. Advances in therapy and educational opportunities for the handicapped have increased both the life span and quality of life for many of those affected by genetic disorders. Recent developments in clinical and laboratory genetics have made possible the better delineation of certain malformation and/or mental retardation syndromes, so that their mode of inheritance can be understood. This information enables the genetic counselor to predict the risk for occurrence of a large number of genetic disorders. Most genetic counseling is done, however, only after the birth of at least one affected individual has alerted the family to their predilection for having children with a genetic disorder. The carrier state of a certain number of genetic disorders can now be detected, so that even before the birth of their first child, a family can be forewarned that they are at increased risk. Previously this knowledge often influenced couples to decide against having any children. The advent of prenatal diagnosis of genetic disease, however, which was pioneered in the 1960s, allows specific diagnoses of inherited disorders in the fetus; parents no longer have only a mathematical risk figure for guidance. The technics which permit a preview of the genotype of the fetus with respect to a certain disorder constitute an exciting new field or medicine. They are not now available for use in routine pregnancies, but in high-risk situations the collaboration of the primary care physician and the medical geneticist can contribute significantly to the prevention of certain severely handicapping genetic disorders. The field is new and promises to offer much more in the future as more of the inherited disorders are biochemically characterized and become subject to prenatal detection.

Amniocentesis↗
PubMed1978

The prenatal diagnosis of genetic disorders.

Prenatal diagnosis has proven highly effective in assessing the status of fetuses at risk of all cytogenetic and of several biochemical and structural disorders with genetic etiologies. The original methodology, based on the cytogenetic and biochemical analysis of cultured amniotic fluid cells, has now been complemented by a wide variety of new techniques. These include several methods for fetal visualization (sonography, fetoscopy, x ray), sampling of fetal blood, and analysis of very small quantities of material. Additional approaches, based on these and other technologies, are likely to permit the prenatal diagnosis of an ever increasing number of genetic disorders. At the same time, the number of pregnancies monitored will increase as greater resources become available and as screening programs identify couples at risk of having genetically abnormal children prior to the birth of an affected child. Prenatal diagnosis is already a powerful means of preventing the birth of individuals with significant genetic defects, thereby sparing both individuals and society from the burdens that such disorders produce. In the future, it is likely to be even more effective.

Amniotic Fluid↗
PubMed1979

Vitamin D-resistant rickets. A prototype of nutritional management of a genetic disorder.

The discovery of the vitamin D endocrine system has opened up many possibilities in our understanding of metabolic bone disease. Of particular importance is the fact that we can now manage certain genetic disorders resulting in vitamin D-resistant rickets or vitamin D-resistant hypocalcemia with the new active hormonal forms of vitamin D and with intelligent dietary management to provide for correction of the mineral difficulty. Thus, in the case of vitamin D dependency, replacement need only be with the missing hormone, 1,25-(OH)2D3. On the other hand, familial hypophosphatemia requires adjustment of the plasma phosphorus by frequent administration of oral phosphate and the adjustment of intestinal calcium absorption by 1,25-(OH)2D3. Renal failure patients require the adjustment of plasma phosphorus concentration and parathyroid hormone status, and the administration of the missing hormone 1,25-(OH)2D3. Hypoparathyroid patients require oral calcium plus 1,25-(OH)2D3, and premature infants require administration of the 1,25-(OH)2D3 because the immature kidneys and immature parathyroid glands fail to produce the required amount of this hormone. Other vitamin D-resistant rachitic conditions cannot be discussed here for lack of space and for lack of information. Undoubtedly, such patients as those having rickets secondary to renal tubular acidosis and rickets secondary to hepatic disorders will eventually come under effecti dietary and hormonal management. In this sense, the vitamin D endocrine system and vitamin D-resistant rickets can serve as a prototype of management of a genetic disorder by dietary means.

Calcium↗
PubMed1978

Electron microscopy in the early diagnosis of genetic disorders of the skin.

Electron microscopy is shown to represent an effective tool in the early diagnosis of genetic disorders. On the basis of ultrastructural findings in various dominant and recessive types of ichthyoses and epidermolyses, defects of structural proteins of the skin proved to form the main intrinsic pathogenetic feature of some dominantly inherited types whereas quantitative impairments characterize their closely resembling recessive counterparts. Most of the diseases concerned severely disable the involved patients. Early diagnosis is therefore of high importance. In those cases where an exact diagnosis in newborn children is difficult or impossible with respect to their clinical features, electron microscopy provides the clinician with reliable and significant criteria to differentiate between closely resembling entities.

Epidermolysis Bullosa↗
PubMed1978

Prenatal diagnosis of genetic disorders.

Sampling of amniotic fluid, visualization of the fetus, fetal blood sampling, and screening of maternal blood represent successive approaches to the diagnosis of specific genetic disorders in the second trimester of pregnancy. Clinical and ethical concerns about the appropriateness, safety, and efficacy of the techniques have led to multidisciplinary assessments at an early stage. A major growth in demand for medical and educational genetic services can be anticipated.

Adult↗
PubMed2025

Data-driven consideration of genetic disorders for global genomic newborn screening programs.

PURPOSE: Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes. METHODS: We assembled a data set comprising 25 characteristics about each of the 4390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion and developed a machine learning model to rank genes for public health consideration. RESULTS: Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%), and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (area under the curve = 0.915, R2 = 84%). CONCLUSION: The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.

Humans↗
PubMed1978

Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions.

We studied 40 patients in 15 families from the Portuguese Azores Islands. Each family was affected by an autosomal dominant genetic disorder. Symptoms began between ages 20 and 50. Ataxia, ophthalmoplegia, pyramidal signs, dystonia, rigidity, and distal atrophy were the major clinical findings. Evidence suggested that this was a single genetic disease, with variable phenotypic expression. Machado disease, nigrospinodentatal degeneration with nuclear ophthalmoplegia, and autosomal dominant striatonigral degeneration may be variations of this same genetic disease.

Adult↗
PubMed1979

Juvenile and late onset forms of depressive disorder: genetic and biological characterization of bipolar and unipolar illness-a review.

The age of onset of depressive illness may have an association with the genetic character and clinical course of the disorder. There are several genetic models of depressive disorder that are based on differences in age of onset. According to a multifactorial model, for example, a late onset would indicate a small genetic and greater environmental component. A correlation has been found between positive family histroy of affective illness and early age of the first episode. The presence or absence of a family history of affective illness has also been found to be distinguished by pharmacology, physiology, symptomatology, and severity. It is therefore recommended, for purposes of diagnosis and treatment, that a family history be gathered for patients with depressive illness.

Adolescent↗
PubMed2026

An EHR-based framework for modeling growth curves and constructing growth centile charts for genetic disorders.

Growth modeling is central to human genetics, as deviations from typical growth can signal an underlying disorder. In this cohort study, we developed a generalizable framework for generating growth charts across genetic conditions using electronic health records (EHR). Leveraging 22 years of longitudinal EHR data from 452,470 patients across 15 genetic conditions and unaffected individuals, we generated sex- and condition-specific growth charts using Generalized Additive Models for Location, Scale, and Shape, and quantified differences in size, timing, and intensity using SuperImposition by Translation and Rotation (SITAR). SITAR-derived growth parameters showed strong concordance with established annotations in OMIM and Orphanet, and identified previously unreported growth patterns. We stratified cystic fibrosis by CFTR functional class and observed greater growth impairment in individuals with homozygous minimal-function variants compared to those with residual function. This framework provides a generalizable approach for leveraging EHR data to refine genotype-phenotype relationships and enable continuous updating of growth charts across genetic conditions.

Journal Article↗
PubMed2026

Optimizing Control Definitions in Opioid Use Disorder Genetic Research Using Electronic Health Records.

Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome-wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure ('generic') versus minimally opioid-exposed control ('exposed'). First, at the phenotypic level, we conducted phenome-wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD-related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16 ± 0.07 vs. 0.10 ± 0.07), associations with the coding OPRM1 variant rs1799971 (pgeneric = 8.83E-03 vs. pexposed = 1.83E-02) and genetic correlations with prior OUD GWAS (rg-generic = 0.83 ± 0.26 vs. rg-exposed = 0.78 ± 0.27). Although GWASs were limited by sample size (Ngeneric = 6269, Nexposed = 6365), compared to an independent OUD GWAS (N = 425 944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.

Humans↗
PubMed2026

Cumulative microscopy reveals cellular states in fibroblasts from patients with genetic disorders.

Analysis of cellular states and signaling trajectories can provide insights into causes of disease. We developed cumulative microscopy, a method to perform cyclical imaging without elution or quenching steps. Cumulative microscopy computationally extracts individual signals from accumulating fluorescence during sequential imaging. We use cumulative microscopy to quantitatively assess cell cycle and stress markers in individual primary fibroblasts from patients with rare genetic proliferative disorders with increased cancer risk. Neural network-based analysis of cumulative microscopy data suggests that cells from patients with Cartilage-hair hypoplasia (CHH), but not Mulibrey Nanism (MUL), show replication stress. We analyze cell states and cell trajectories and find that a subset of cells from patients with CHH show spontaneous replication stress, followed by cell cycle exit in both G1 and G2 phases. We note that replication stress potentially could underlie both proliferative defects and increased cancer risk in CHH patients and conclude that cumulative microscopy is an efficient, quantitative, and generalizable approach to multiplex microscopy.

Humans↗