Genetic conditions are individually rare but are common in aggregate, and they often present in the neonatal and early pediatric periods. These conditions are often severe, can be difficult to diagnose and manage, and may heavily affect patients, families, health care systems, and society. Because of recent technological advances, the availability and uptake of genetic and genomic testing are increasing rapidly. However, there is a dearth of trained geneticists and genetic counselors to help guide and explain these conditions and relevant tests. To help hospitalists, neonatologists, and related practitioners navigate this complex and evolving field, we have compiled a list of free (mostly Web-based) resources relevant to the diagnosis and management of genetic conditions and related disorders. These resources, which we describe individually, can be useful for nongeneticist clinicians, and some also include material that can be used to explain concepts and conditions to patients or families. The resources presented are divided into the following categories (which overlap): general information, databases of genetic conditions, resources that can help generate differential diagnoses, databases of genetic testing laboratories (to help with logistics of ordering tests), information on newborn screening, and other resources. We also include a separate list of helpful textbooks and manuals. We conclude with 2 examples describing how some of these resources would be used by a pediatric hospitalist or neonatologist during the inpatient management of a child with a suspected genetic condition.
Genetic and genomic disorders are individually rare but are common in aggregate. Approximately 3% to 5% of infants are born with a congenital anomaly or genetic disorder.1,2 By age 25, an older study estimated that ∼8% of individuals in the overall population are recognized as being affected with these types of diseases.3 The National Institutes of Health and rare disease advocacy groups generally concur with this estimates, citing 10% of the population as affected with a rare disease, 80% of ascribed to genetic causes (see https://rarediseases.info.nih.gov/; https://globalgenes.org/; https://rarediseases.org/). These conditions are often severe, can be difficult to diagnose and manage, and can heavily affect patients, families, the health care system, and society.4–6
There are thousands of disorders with known genetic causes. More than 3000 individual genes are known to cause monogenic or Mendelian genetic diseases; this number does not represent genetic diseases caused by other mechanisms such as large deletions involving multiple genes, whole chromosome aneuploidy, or somatic mutations (as seen in some cancers and congenital disorders).7 It is important to also note that this number does not represent genetic diseases caused by processes such as epigenetics, a complex phenomenon involving modification of gene expression or activity rather than alteration of the genetic code. Recent technological breakthroughs have allowed the identification of previously unknown causes of genetic conditions at an unprecedented rate, with >14 new “disease genes” currently published each month.8,9 These advances in technology create a genetic testing atmosphere with a dizzying number of options that is also in a constant state of growth and change. In addition, there is a shortage of clinical geneticists and genetic counselors to provide guidance, interpretation, and support for both patients and clinicians.10
There is growing evidence that early molecular diagnosis (ie, finding the exact cause of the condition) for patients with genetic disorders is both medically and financially beneficial.11,12 In addition to avoiding costly “diagnostic odysseys” and possible related iatrogenic complications, finding the cause of a condition can allow the possibility for direct interventions, more tailored patient care, and informed counseling and decision-making.7
Because many genetic disorders present in the early pediatric period and direct input from genetic specialists is not always immediately available, our specific aim was to prepare a list of mostly free, Web-based resources (those with mobile apps currently available are also mentioned) that can be helpful for clinicians (and researchers) who may encounter and treat these patients.
This list of resources was compiled through a survey of clinical genetic counselors and geneticists in different specialty areas (prenatal, neonatal, pediatric, and adult medicine) and in both outpatient and inpatient clinical settings to determine which resources they and their nongeneticist colleagues found the most useful in areas related to patient care. We also reached out to bioinformaticians and laboratory genetic counselors and personnel for additional recommendations. All of the Web sites were used by ≥1 medical professional who was surveyed. This list is not meant to supplant formal genetic consultation and counseling but rather to provide reliable, readily accessible information that may help educate clinicians and provide navigation through this complex field.
We have divided the resources into sections based on the primary type of use. However, some assignments are challenging because many of the resources might have multiple types of uses. Finally, although there are many other such resources available, we have intentionally excluded those that, based on feedback from our internal group and from nongeneticist clinicians, are judged to be more appropriate for genetic specialists, are focused only on specific conditions or disorders, or are free to. We have included links to each site and literature citations where available. It is important to note that some links to the provided resources might have changed since this article was initially written, but search engines may be used to identify the current address.
Included at the end of the online resource section is a list of relevant textbooks, manuals, and related written references. Table 1 lists free, Web-based resources. Table 2 lists recommended textbooks and additional resources. Although the main focus of this article is to enumerate free, Web-based resources, we thought it was important to include some essential textbooks that incorporate clinically relevant information about various genetic conditions.
Centers for Disease Control and Prevention http://www.cdc.gov/genomics/
The Centers for Disease Control and Prevention Web site contains areas dedicated to many relevant issues, including basic descriptions of genetics and genomics and related concepts, resources related to family history, condition-specific information, newborn screening, and highlights pertaining to particular current events involving genetics and genomics. Users can also subscribe to a weekly e-mail that includes topics of their choosing (http://www.cdc.gov/Other/emailupdates/).
Genetics Home Reference: http://ghr.nlm.nih.gov/
Genetics Home Reference (GHR), which has recently undergone large-scale retooling, contains a great deal of information about genetic and genomic terminology and user-friendly descriptions of many common genetic conditions. Drop-down sections include information on the prevalence, genetic changes, inheritance pattern, diagnosis, and management associated with each condition. Numerous links to additional information and resources for both medical professionals and families are provided, including a section titled “Help Me Understand Genetics” (https://ghr.nlm.nih.gov/primer).
National Coalition for Health Professional Education in Genetics: http://www.nchpeg.org/
The National Coalition for Health Professional Education in Genetics (NCHPEG) Web site includes several types of formal education on genetics and genomics and fact sheets on current issues, such as noninvasive prenatal testing (a recent method of prenatal screening for chromosomal and related disorders) and the Genetic Information Nondiscrimination Act (a law created to protect patients from genetic discrimination by health insurance companies and employers). The “Point of Care” pages (under the Products and Programs heading: http://www.nchpeg.org/index.php?option=com_content&view=article&id=26&Itemid=64) also mention a number of useful resources, including “genetic red flags,” family history information and tools, and patient-friendly terminology for discussing genetics with patients.
National Human Genome Research Institute: https://www.genome.gov/
The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, hosts a Web site that includes information aimed at scientists, patients, and clinicians. Among other resources (such as explanations of the Genetic Information Nondiscrimination Act), the “Issues in Genetics” section (https://www.genome.gov/issues/) covers hot topics that frequently come up in discussions of the field, and there is a section (https://www.genome.gov/27527599/genetics-and-genomics-for-health-professionals/) specifically designed for clinicians.
Clinical Genomic Database: http://research.nhgri.nih.gov/CGD/
The Clinical Genomic Database (CGD)7 contains a list of all single-gene disorders resulting from germline mutations. The CGD focuses on briefly describing medical interventions that would be indicated from finding a mutation in a disease-related gene.
GeneReviews includes individual, periodically updated articles on clinical, diagnostic, and molecular aspects of many genetic disorders (usually written by a world expert on the particular condition). The individual articles can be found through the “GeneReviews” tab on the Genetic Testing Registry (GTR) homepage or through the National Center for Biotechnology Information ( http://www.ncbi.nlm.nih.gov/books/NBK1116/). Importantly, each of these articles includes information about diagnosis (both clinical and molecular), surveillance, ongoing management, genetic counseling, and support resources. Other information is available through the other GTR tabs, such as laboratories where testing is available (see details below, in the Laboratory and Testing Databases section).
Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim
Online Mendelian Inheritance in Man (OMIM), 1 of the longest-standing genetic databases, evolved from a printed resource. It contains overlapping information on genes and genetic conditions and may be searched based on either. OMIM may also be used to generate differential diagnoses from a list of symptoms or features. For patients with known or suspected genetic conditions, OMIM can be helpful for learning about historical aspects of a condition and characteristic clinical findings.
Differential Diagnosis Generators (see also OMIM)
The Phenomizer13,14 can be used to generate differential diagnoses for patients with suspected genetic disorders. The output differential, which is statistically calculated, includes both conditions with known genetic causes and syndromes without identified etiologies. To use the Phenomizer, clinicians input observed clinical features and can also use the inheritance pattern. The clinical features that can be selected are standardized and based on human phenotype ontology terms (see http://www.human-phenotype-ontology.org/). An app-based version is also available. Note that the free software version is available only for academic instruction and research use, and commercial licenses are available.
Face2Gene uses facial recognition algorithms to create differential diagnoses by using patient facial photos that can be uploaded via computer or through their apps (with patient consent). In addition to photos, the presence or absence of other features can be used to inform the differential diagnosis. Cases with unknown diagnoses can also be submitted to an electronic mailing list where participating dysmorphologists and geneticists can comment and make testing recommendations. An app-based version is also available, and the company has produced a small booklet focusing on dysmorphology.
Individual clinicians can use a free version to input pertinent positives and negatives; output includes a ranked differential diagnosis, a list of applicable tests for definitive diagnosis, and a note generator. Other versions are available for reference laboratories and through accounts for health systems to integrate electronic health record data.15,16
Laboratory and Testing Databases (see also GeneReviews)
GeneTests is a medical genetics resource that includes a national and international laboratory directory, clinic directory, and links to other resources such as GeneReviews, OMIM, and GHR (see above for descriptions). Tests can be searched by gene, condition, or test name; output includes laboratories that do testing, test method, and turnaround time and price (when available).
Genetic Testing Registry: http://www.ncbi.nlm.nih.gov/gtr/
GTR includes links to genetic test information as submitted by both US-based and international laboratory providers. As part of the National Center for Biotechnology Information, GTR provides links (see http://www.ncbi.nlm.nih.gov/gtr/docs/resources/) to other resources such as ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/), a database of genetic variants and the evidence about whether they are related to disease, and MedGen (http://www.ncbi.nlm.nih.gov/medgen), a database on attributes of genetic conditions.
NextGxDx offers a service that finds all clinical laboratories that offer genetic testing, including enzyme studies and biochemical tests. The site allows searches by gene, condition, or test (such as for whole-exome sequencing), and displays prices, turnaround times, and links to the individual laboratory Web sites. The Web site also offers a fee-for-service option for direct testing.
American College of Medical Genetics and Genomics: https://www.acmg.net/
As expected for the official college site, there are many relevant resources available at the American College of Medical Genetics and Genomics (ACMG) Web site. One especially helpful resource involves newborn screening (https://www.acmg.net/ACMG/Publications/ACT_Sheets_and_Confirmatory_Algorithms/ACMG/Publications/ACT_Sheets_and_Confirmatory_Algorithms/ACT_sheets_Homepage.aspx?hkey=6d43e3d3-71fd-49f4-88d5-7197238f9f33). The ACMG “ACT Sheets and Confirmatory Algorithms” contain specific instructions for handling positive results for every condition tested for in newborn screening.
National Newborn Screening & Global Resource Center http://genes-r-us.uthscsa.edu/
The National Newborn Screening & Global Resource Center (NNSGRC) is an independent national resource center for newborn screening. Among other helpful resources, there are links to each state’s newborn screening contact person for the newborn screening laboratory and for the follow-up program.
Previously called Organization of Teratology Information Specialists (OTIS), this Web site includes information for patients and clinicians on medications and other exposures during pregnancy or breastfeeding. In addition to items such as fact sheets on FAQs and links to studies, the Web site includes mechanisms (phone, e-mail, and live chat) to get in touch with experts to help answer questions.
The Pharmacogenomics Knowledgebase: https://www.pharmgkb.org/
The Pharmacogenomics Knowledgebase (PharmGKB) is a knowledge resource that includes clinically relevant information related to pharmacogenetics and pharmacogenomics. Resources on PharmGKB include dosing guidelines, drug labels, and actionable gene–drug associations. For the most clinically relevant drug–gene interactions, Clinical Pharmacogenetic Implementation Consortium guidelines are available through the Web site (https://cpicpgx.org/guidelines/).
Clinical Significance and Genetic Counseling for Common Ultrasound Findings: http://nsgc.org/p/cm/ld/fid=232
The latest edition of this book provides updates on the significance of ultrasound findings, including those suggesting the presence of a genetic condition, and information to help determine whether and what type of additional prenatal or postnatal testing, follow-up, and counseling should be offered.
Emery and Rimoin’s Principles and Practice of Medical Genetics
This multivolume (the latest edition is fully available online) book includes sections on diverse aspects of genetics in clinical practice, including related to concepts, research approaches, and individual conditions.17
The Encyclopedia of Genetic Disorders and Birth Defects
This text offers lay readers and professionals a reference to congenital disorders and birth defects. This volume contains more than >1000 entries, appendices providing tables of statistics, directories of service and support groups, and an introductory history of human genetics.18
Gorlin’s Syndromes of the Head and Neck
This dysmorphology-focused text describes several hundred genetic syndromes involving structural defects affecting the head and neck. Additional sections include information on teratogens, deformation sequences, physical measurements and growth curves, and useful resources.19
Human Malformations and Related Anomalies
This reference book on malformations is organized by body system and provides pertinent information on each anomaly, including clinical variability, known and hypothesized causes, associated anomalies and syndromes, and management and prognosis.20
Management of Genetic Syndromes
This book includes individual chapters focusing on the diagnosis and management of 59 different genetic conditions and is written to be useful to both geneticists and nongeneticist clinicians.21
Signs and Symptoms of Genetic Conditions
Comprising 31 clinical protocols from leading clinical geneticists, this book provides a practical manual for the diagnosis and management of common human genetic conditions based on their presenting signs and symptoms. Each chapter examines a specific clinical finding and leads the user through a step-by-step approach to a differential diagnosis.22
Smith’s Recognizable Patterns of Human Malformation
Smith’s Recognizable Patterns of Human Malformation is a long-standing resource for malformation syndromes of environmental and genetic etiology and recognizable disorders of unknown cause. This book provides concise yet accessible guidance to help diagnose these disorders, establish prognoses, and provide appropriate management and genetic counseling. As the title suggests, the descriptions also include multiple patient photographs to aid in recognizing the patterns of physical features.23
Vademecum Metabolicum: http://www.amazon.com/Vademecum-Metabolicum-Johannes-Zschocke/dp/3794528166
This pocket-sized manual (with a recognizable yellow cover) includes compact reviews of inborn errors of metabolism from a clinically oriented perspective. The manual includes a section on evaluating signs and symptoms of metabolic disorders in the context of various clinical situations, including neonatal-onset disease, and can be helpful in interpreting metabolic and biochemical laboratory results.
To emphasize the utility and importance of such resources in a clinical setting, 2 representative case scenarios are provided.
A male term infant (39 weeks’ gestational age) with a history of intrauterine growth restriction and failure to thrive is transferred to the NICU shortly after delivery because of respiratory insufficiency. His immediate birth measurements are notable for microcephaly (head circumference <3rd centile for gestational age). His respiratory insufficiency improves, and after spending 5 days in the NICU, the infant is discharged from the hospital. Two weeks later, however, the patient is readmitted to the inpatient pediatric ward for feeding difficulties and poor weight gain. Upon physical examination of the infant by the pediatric hospitalist team, dysmorphic features are noticed, including large ears. There is no obvious syndromic explanation, and family history is noncontributory. On careful examination based on feeding difficulties, the child is also noted to have a posterior cleft palate. An echocardiogram, performed because of a suspected pathologic murmur, shows aortic coarctation.
With this constellation of findings, it would be important to have a geneticist or genetic counselor perform a full consultation. If a genetic specialist is not immediately available (which is often the case), a clinician might start with a differential diagnosis generator Web site such as Phenomizer (which uses clinical features) or Face2Gene (which uses photographs of the patient, with appropriate consent, and clinical features) to help assess the child. These Web sites use clinical information to assist in forming a differential diagnosis.
On the third day of readmission, the infant undergoes a formal genetic consultation, and dysmorphology examination reveals long palpebral fissures with eversion of the lateral portion of the lower eyelid, tented upper lip, and prominent fingertip pads. The genetics team raises concern for the possibility of Kabuki syndrome and suggests testing for mutations in genes associated with this condition. To learn more about this condition to optimize patient care and facilitate family counseling at this point, the hospitalist team turns to GHR, OMIM, and GeneReviews. These various resources explain complex genetic information in both physician-friendly (nongeneticist) and patient-friendly text. The pediatric hospitalist also uses the NextGxDx Web site to check specimen requirements and turnaround times for the commercial genetic testing laboratory suggested by the geneticist.
Approximately 1 month later, after the child has been discharged from the hospital, the test result comes back positive for a mutation in the gene KMT2D, 1 of the genes related to Kabuki syndrome. The hospitalist team sends the result to the child’s outpatient pediatrician. The hospitalist, anticipating that this child may be readmitted, and the outpatient pediatrician review the condition and management recommendations in GeneReviews and the CGD.
An 18-month-old boy of Caucasian ancestry was healthy until a recent illness after an upper respiratory infection, which had also been present in multiple household members. His parents brought him to the emergency department after ∼1 week of worsening respiratory symptoms. He was admitted to the hospital for signs of heart failure, and a dilated cardiomyopathy was noted via echocardiogram. Incidentally, his blood work showed neutropenia. Family history is notable for a maternal uncle with a history of dilated cardiomyopathy diagnosed in his teens because of exercise intolerance. No additional family members have obvious signs or symptoms of dilated cardiomyopathy by report. Because of the family history, multiple family members, including the patient’s mother, have undergone echocardiograms, which have been negative by report. The patient has a healthy and asymptomatic 4-year-old sister.
With this strong history of dilated cardiomyopathy in male family members, it would be important to have a geneticist or genetic counselor perform a full consultation. While awaiting a formal genetics consultation, a clinician might start with a differential diagnosis generator Web site such as Phenomizer, which allows key clinical findings to be used to generate a list of potential syndromes and conditions.
On the second day of admission, the patient undergoes a formal genetics consultation, and the dysmorphology examination indicates a round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes. The geneticist and the genetic counselor bring up the possibility of Barth syndrome and recommend preliminary plasma amino acids and urine organic acids to be ordered. As a hospitalist you look at GeneReviews before ordering the samples to be collected and see that a preliminary diagnosis of Barth syndrome can be made through genetic testing of the involved gene if the initial tests appear positive. This information helps in discussion with the family during evening rounds.
The urine and blood test results come back and show significantly elevated urine 3-methylglutaconic acid (3-MGC), which indicates Barth syndrome. As a hospitalist you are aware that every state has different recommendations and requirements for newborn screening, and you wonder whether elevated 3-MGC would have been seen when this patient was born. You check the patient’s chart and see that this baby was born in Louisiana. Consulting a Web site such as the NNSGRC, you confirm that 3-MGC is not currently on the state’s newborn screening panel.
The geneticist and genetic counselor recommend for additional confirmation of Barth syndrome to order genetic testing of the TAZ gene. You use OMIM to investigate the TAZ gene and find out that it is the only gene known to be associated with Barth syndrome.
Given the significantly elevated risk of heart failure in patients with Barth syndrome, the hospitalist, anticipating that this child may be readmitted, reviews the condition and management recommendations in GeneReviews and the CGD. Upon the boy’s eventual hospital discharge, with close cardiology, genetics, and immunology follow-up arranged for the child, the patient’s mother asks you whether her 4-year-old daughter should undergo genetic testing also. She has talked with the genetics team about this question but wants to review the information. First, you review inheritance with the patient’s mother and father by providing pictures downloaded from a patient-friendly Web site such as GHR. You then review the literature on the NHGRI Web site, which has various articles referencing the need for autonomy for testing asymptomatic family members who would at most be carriers of genetic conditions.
The resources described in this article may be used to aid in diagnosis, education, and patient communication. This information is especially important because of the frequent discoveries that are transforming the field of genetics and many related areas of medicine, including inpatient pediatric care.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Solomon is managing director of GeneDx, a subsidiary of the company BioReference, which owns GeneTests, a Web site described in the manuscript. GeneDx also provides clinical genetic testing, although this company is not discussed in the article. Dr Solomon is the curator of the Clinical Genomic Database but does not receive any royalties, compensation, or other revenue. Dr Solomon receives royalties as co-editor of the textbook Human Malformations III (Oxford University Press). The other authors have indicated they have no potential conflicts of interest to disclose.
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