Kathryn B. Garber

Fragile X syndrome.

Fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is associated with intellectual and emotional disabilities ranging from learning problems to mental retardation, and mood instability to autism. It is most often caused by the transcriptional silencing of the FMR1 gene, due to an expansion of a CGG repeat found in the 5′-untranslated region. The FMR1 gene product, FMRP, is a selective RNA-binding protein that negatively regulates local protein synthesis in neuronal dendrites. In its absence, the transcripts normally regulated by FMRP are over translated. The resulting over abundance of certain proteins results in reduced synaptic strength due to AMPA receptor trafficking abnormalities that lead, at least in part, to the fragile X phenotype.

Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes

Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a ‘best practice’ for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.

Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome.

15q13.3 deletion syndrome (15q13.3DS) is a common recurrent genomic disorder associated with epilepsy, intellectual impairment, aggressive behavior, schizophrenia, and autism. A 39‐year‐old male presented with 15q13.3DS, epilepsy, intellectual impairment, psychosis, and recurrent episodes of aggressive rage. We hypothesized that the patients aggressive behavior reflected deficits in α7 nicotinic cholinergic receptor (NChR)‐mediated neurotransmission, arising from haploinsufficiency of the structural gene CHRNA7 due to the deletion. Treatment with the NChR allosteric modulator and acetylcholinesterase (AChE) inhibitor, galantamine, led to a dramatic decline in the frequency and intensity of rage outbursts, suggesting that enhancement of α7 NChR function can ameliorate 15q13.3DS‐associated rage outbursts.

Reassessment of Genomic Sequence Variation to Harmonize Interpretation for Personalized Medicine

Accurate interpretation of DNA sequence variation is a prerequisite for implementing personalized medicine. Discrepancies in interpretation between testing laboratories impede the effective use of genetic test results in clinical medicine. To better understand the underpinnings of these discrepancies, we quantified differences in variant classification internally over time and those between our diagnostic laboratory and other laboratories and resources. We assessed the factors that contribute to these discrepancies and those that facilitate their resolution. Our process resolved 72% of nearly 300 discrepancies between pairs of laboratories to within a one-step classification difference and identified key sources of data that facilitate changes in variant interpretation. The identification and harmonization of variant discrepancies will maximize the clinical use of genetic information; these processes will be fostered by the accumulation of additional population data as well as the sharing of data between diagnostic laboratories.

Towards Understanding RNA-Mediated Neurological Disorders

RNA-mediated mechanisms of disease pathogenesis in neurological disorders have been recognized in the context of certain repeat expansion disorders. This RNA-initiated neurodegeneration may play a more pervasive role in disease pathology beyond the classic dynamic mutation disorders. Here, we review the mechanisms of RNA toxicity and aberrant RNA processing that have been implicated in ageing-related neurological disorders. We focus on diseases with aberrant sequestration of RNA-binding proteins, bi-directional transcription, aberrant translation of repeat expansion RNA transcripts (repeat-associated non-ATG (RAN) translation), and the formation of pathological RNA:DNA secondary structure (R-loop). It is likely that repeat expansion disorders arise from common mechanisms caused by the repeat expansion mutations. However, the context of the repeat expansion determines the specific molecular consequences, leading to clinically distinct disorders.

Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing.

Purpose:As exome and genome sequencing using high-throughput sequencing technologies move rapidly into the diagnostic process, laboratories and clinicians need to develop a strategy for dealing with uncertain findings. A commitment must be made to minimize these findings, and all parties may need to make adjustments to their processes. The information required to reclassify these variants is often available but not communicated to all relevant parties.Methods:To illustrate these issues, we focused on three well-characterized monogenic, metabolic disorders included in newborn screens: classic galactosemia, caused by GALT variants; phenylketonuria, caused by PAH variants; and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, caused by ACADM variants. In 10 years of clinical molecular testing, we have observed 134 unique GALT variants, 46 of which were variants of uncertain significance (VUS). In PAH, we observed 132 variants, including 17 VUS, and for ACADM, we observed 64 unique variants, of which 33 were uncertain.Conclusion:After this review, 17 VUS (37%; 7 in ACADM, 9 in GALT, and 1 in PAH) were reclassified from uncertain (6 to benign or likely benign and 11 to pathogenic or likely pathogenic). We identified common types of missing information that would have helped make a definitive classification and categorized this information by ease and cost to obtain.Genet Med 19 1, 77–82.

The virtual diagnostic laboratory: A new way of teaching undergraduate medical students about genetic testing

Purpose: Medical students often perceive genetics as a discipline focused on rare diseases with relevance only to genetics specialists. Because genetic testing has now infiltrated most if not all medical disciplines, we need new teaching approaches to help trainees incorporate emerging genetic testing strategies appropriately into medical practice. With the ever-increasing number of known disease-associated genes, it is also important to shift from a paradigm of memorization to one of critical evaluation and an awareness of available resources.Methods: We designed case-based virtual laboratory sessions for first-year medical students at Emory University. These sessions emphasize both rare and common health issues and allow the students to practice applying their fundamental genetics knowledge in the diagnostic setting.Results: These sessions proved a valuable approach to presenting the intricacies of diagnostic genetic testing. Students rate the sessions very highly, with 92% of them agreeing or strongly agreeing that the sessions had educational value. The students commented that ours was an effective approach to teaching the material that illustrates well the impact of genetics on patient care.Conclusions: The virtual diagnostic laboratory approach is an effective, nonlecture-based method of teaching medical students about genetic testing strategies and their application in the clinical setting.

Cleft palate in a multigenerational family with a microdeletion of 20p12.3 involving BMP2

Cleft palate (CP) is a frequent and recognizable birth defect attributed to a variety of etiologies including genetic abnormalities and environmental exposures. Bone morphogenetic proteins (BMPs) are involved in embryonic signaling important for a number of developmental processes including bone formation and palate morphogenesis. Recently, haploinsufficiency of BMP2 was associated with syndromic forms of CP. Here, we report on a multigenerational family with a history of CP as a result of a 2.3 Mb deletion of chromosome 20p12.3, including the BMP2 gene. In addition to a submucous CP, the probands clinical phenotype included failure to thrive (FTT), global developmental delays (DD), and dysmorphic features. The affected father exhibited an overt CP, with a facial gestalt and minor dysmorphic features similar to the proband. The father was otherwise healthy with no history of FTT or DD, suggesting high penetrance, yet variable expressivity for haploinsufficiency of BMP2. The findings presented here provide further evidence for the role of BMP2 in syndromic forms of CP.

Participatory Genomic Testing as an Educational Experience.

Several institutions have incorporated participatory genomic testing into their curricula to engage students in experiential learning, and this has raised ethical concerns. We summarize strategies for managing these concerns and review evidence of the influence of this experiential approach on student knowledge and attitudes towards genomics.

Scaling resolution of variant classification differences in ClinVar between 41 clinical laboratories through an outlier approach

ClinVar provides open access to variant classifications shared from many clinical laboratories. Although most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences (MSDs). Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with MSDs between the laboratories (650 variants). Next, MSDs were filtered for variants with ≥3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications, which will improve the care of patients with, or at risk for, genetic disorders.