Laurie A. Demmer

Clinical genetic testing for patients with autism spectrum disorders

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%–2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%–0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%–21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%–8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

Recommendations for the integration of genomics into clinical practice

The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES, especially as health-care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remain a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health-care providers to understand its benefits and limitations in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. New, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held that brought together physicians, laboratorians, scientists, genetic counselors, trainees, and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This article provides recommendations that will guide the integration of genomics into clinical practice.Genet Med 18 11, 1075–1084.

Mouse model implicates GNB3 duplication in a childhood obesity syndrome

Significance We describe a genomic disorder that causes obesity, intellectual disability, and seizures. Children with this syndrome carry an unbalanced chromosome translocation that results in the duplication of over 100 genes, including G protein β3 (GNB3). Although GNB3 polymorphisms have been associated with obesity, hypertension, and diabetes, the mechanism of GNB3 pathogenesis is unknown. We created a transgenic mouse model that carries a duplication of GNB3, weighs significantly more than wild-type mice, and has excess abdominal fat. GNB3 is highly expressed in the brain and may be important for signaling related to satiety and/or metabolism. Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity. This unbalanced chromosome translocation leads to duplication of over 100 genes on chromosome 12, including the obesity candidate gene G protein β3 (GNB3). We generated a transgenic mouse model that carries an extra copy of GNB3, weighs significantly more than its wild-type littermates, and has excess intraabdominal fat accumulation. GNB3 is highly expressed in the brain, consistent with G-protein signaling involved in satiety and/or metabolism. These functional data connect GNB3 duplication and overexpression to elevated body mass index and provide evidence for a genetic syndrome caused by a recurrent CNV.

Professional Medical Education and Genomics

Genomic medicine is a relatively new concept that involves using individual patients genomic results in their clinical care. Genetic technology has advanced swiftly over the past decade, and most providers have been left behind without an understanding of this complex field. To realize its full potential, genomic medicine must be both understood and accepted by the greater medical community. The current state of professional medical education in genomics and genomic medicine is reviewed, including ongoing plans to expand educational efforts for medical students, clinical geneticists, and nongeneticist physicians.

Maternal Tea Consumption during Early Pregnancy and the Risk of Spina Bifida

Studies have demonstrated that catechin, an antioxidant found in tea, can reduce the bioavailability of folate. Because periconceptional folic acid intake has been demonstrated to reduce the risk of spina bifida, tea consumption may put pregnant women at risk because of its possible antifolate properties. Using data collected in the Slone Epidemiology Center Birth Defects Study, we examined whether tea consumption during early pregnancy was associated with an increased risk of spina bifida. Mothers of 518 spina bifida cases and 6424 controls were interviewed within 6 months after delivery about pregnancy events and exposures. Data on tea intake were collected during three periods (1976-1988, 1998-2005 and 2009-2010). Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for study center. Intake of both periconceptional food folate and diet and supplemental folic acid were examined as a potential effect modifier. For 1976 to 1988, ORs were not elevated for daily tea intake. For 1998 and onward, ORs were also close to 1.0, but there was a modest increase for those who drank more than 3 cups/day (OR, 1.92; 95% CI, 0.84-4.38). Among women with total folic acid intake greater than 400 μg, consumption of 3 cups or more of tea per day was associated with an increased risk of spina bifida in 1976 to 1988 (OR, 2.04; 95% CI, 0.69-7.66) and in the later periods (OR, 3.13; 95% CI, 0.87-11.33). Our data do not support an overall association between tea consumption and spina bifida, but there is a suggestion of a possible interaction between higher levels of folic acid intake and tea consumption.

Genetics for the pediatric anesthesiologist: a primer on congenital malformations, pharmacogenetics, and proteomics.

Molecular genetics is the study, at the molecular level, of how genetic information is stored, inherited, and expressed and of how it influences the structure and function of cells in health and in disease. Although molecular approaches have been used for decades in the laboratory and are at the core of modern medical education, they are only now beginning to influence clinical practice. A variety of sophisticated techniques permit rapid and affordable DNA sequencing, gene expression profiling, gene cloning, gene manipulation, gene transfer, recombinant protein production, and other technologies of enormous biomedical importance. Success in genomics has spawned additional ambitious endeavors, including proteomics, pharmacogenomics, and bioinformatics. These techniques are providing new diagnostic, prognostic, and therapeutic opportunities in all areas of medicine, including anesthesiology. With the use of molecular criteria and the diminishing cost of analytic technologies, anesthetic practice will become more individualized, and greater emphasis will be placed on the patients genetic makeup. Both surgical and nonsurgical decisions will increasingly accommodate molecular data crucial to perioperative anesthetic management. In this article we have summarized three lectures on congenital malformations, pharmacogenetics, and proteomics presented at the 22nd Annual Meeting of the Society for Pediatric Anesthesia.

A Description of Spina Bifida Cases and Co-Occurring Malformations, 1976–2011

Mandatory folic acid fortification in the United States corresponded with a decline in the prevalence of spina bifida (SB). The aim of this study was to describe the epidemiologic characteristics of isolated versus non‐isolated SB cases in both pre‐ and post‐fortification periods. SB cases in the Slone Epidemiology Center Birth Defects Study from 1976 to 2011 without chromosomal anomalies and syndromes were included. A maternal interview, conducted within 6 months of delivery, collected information on demographics, reproductive history, diet, and supplement use. Daily folic acid intake in the periconceptional period was calculated using both dietary and supplement information and categorized as low intake (<400u2009µg/day) or high intake (≥400u2009µg/day). SB cases (nu2009=u20091170) were classified as isolated (80.4%) or non‐isolated (19.1%). Non‐isolated cases were further divided into subgroups based on accompanying major malformations (midline, renal, genital, heart, laterality). Compared to non‐isolated cases, isolated cases were more likely to be white, non‐Hispanic and have more than 12 years of education. Cases in the renal, genital, and heart subgroups had the lowest proportions of mothers with a high folic acid intake. The change from pre‐ to post‐fortification was associated with a decrease in the proportion of isolated cases from 83% to 72%, though in both periods isolated cases were more likely to be female and their mothers were more likely to have high folic acid intake. These findings highlight the importance of separating isolated and non‐isolated cases in etiologic research of SB.

Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review.

Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot‐Marie‐Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7‐month‐old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next‐generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2‐related CMT2. Our patient with MFN2‐related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation.

The development and implementation of an in-service exam for medical genetics residency programs

Purpose: In-service exams are a commonly used educational tool in postgraduate medical education. Although most specialties utilize such an exam, medical genetics did not. It was decided in the spring of 2009 at the inaugural Medical Genetics Residency Program Directors (PDs) Group meeting to develop and implement such a test.Methods: Using questions sent in from PDs, a 125-question exam was created, with 125 multiple-choice questions according to the format of the National Board of Medical Examiners. The exam covered genetics in the following areas: basic/molecular (~45 questions), cancer and adult (20), prenatal (20), biochemical (20), pediatric/dysmorphology (20). The exam was administered for the first time in February 2010, and again with modifications in 2011.Results: In total, 174 trainees from 35 programs completed the exam in 2010; in 2011 the number increased to 214, representing 39 US programs, and 4 Canadian programs. For both years, most participants were medical genetics residents (106 in 2010; 127 in 2011), but a substantial number of clinical laboratory fellows also participated (68 in 2010; 85 in 2011).Conclusion: The development and implementation of this test were an overall success, in that in two years we were able to secure almost 100% participation from medical genetics residency programs, and that we created an infrastructure to develop and implement this exam on a yearly basis. There is need for improvement, notably in the relatively low mean score and relatively narrow spread of scores. However, we believe that, with efforts under way to improve the quality of the questions, the in-service exam will become a fundamental tool in medical genetics residency education.Genet Med 2012:14(5):552–557