Sarah Macklin

Case report: 5 year follow-up of adult late-onset mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS)

Mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) is a multisystem mitochondrial disorder that typically presents in childhood. We describe the follow-up of a patient who was diagnosed with late-onset MELAS at the age of 49. Her clinical course includes sensorineural hearing loss, seizures, and multiple episodes of stroke-like metabolic crises. Molecular genetic testing on whole blood revealed 31% heteroplasmy of a m.3243A > G variant in the mtDNA, the causative variant in approximately 80% of MELAS cases. The original diagnostic criteria for MELAS required the onset of stroke-like episodes prior to 40 years of age but this case and others demonstrate that onset may be delayed in certain individuals. Therefore, MELAS should be included in the differential diagnosis of stroke-like episodes in patients of any age.

Maple syrup urine disease: mechanisms and management

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients.

Observed frequency and challenges of variant reclassification in a hereditary cancer clinic

PurposeEfforts have been made by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology to make variant classification more uniform, but many limitations remain. Reclassification of a variant of uncertain significance (VUS) is expected, but other more certain calls, like pathogenic or benign, can also be reclassified once additional information is gathered. Variant reclassification can create difficult circumstances for both patients and clinicians.MethodsRetrospective review of all variant reclassifications in genes associated with hereditary cancer syndromes at one clinic between September 2013 and February 2017 was completed. All variant reclassifications were completed and reported by the original testing laboratory.ResultsA total of 1,103 hereditary cancer tests were ordered. Fewer than 5% (40/1,103) of the initial reports were updated during that time period. Most reclassifications (29/40) were downgrades of VUS to likely benign. Only three reclassifications could potentially alter medical management.ConclusionThe majority of variant reclassifications do not impact medical management. Upgrading a variant call to pathogenic could be important for a patient’s care and shows the importance of open communication between laboratories and clinicians. A variant downgrade from pathogenic can be a significant reclassification as well, especially if prophylactic surgery has been completed.

Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1

Pathogenic variants in ryanodine receptor 1 (RYR1, MIM# 180901) are the cause of congenital myopathy with fiber‐type disproportion, malignant hyperthermia susceptibility type 1, central core disease of muscle, multiminicore disease and other congenital myopathies.

The Psychosocial Impact of Carrying a Debated Variant in the GLA Gene

The clinical significance of the c.427G>A (p.A143T) variant in GLA is a topic of debate within the lysosomal storage disease community. A review of the literature and published case reports found the clinical impact of the variant to range from classic Fabry symptoms to healthy unaffected males with normal alpha- galactosidase enzyme levels, leaving clinicians unsure of how to manage these individuals. As the number of states testing for Fabry disease on their newborn screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the p.A143T variant affects those with this change. A self-response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals’ beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the p.A143T variant. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.

Physician interpretation of variants of uncertain significance

A growing number of physicians will interact with genetic test results as testing becomes more commonplace. While variants of uncertain significance can complicate results, it is equally important that physicians understand how to incorporate these results into clinical care. An online survey was created to assess physician self-reported comfort level with genetics and variants of uncertain significance. Physicians were asked to respond to three case examples involving genetic test results. The survey was sent to 488 physicians at Mayo Clinic FL on 8/16/2017. Physicians from all specialties were invited to participate. A total of 92 physicians responded to the survey. Only 13/84 (14.6%) responded to all three case examples with the answer deemed “most correct” by review of literature. Physicians that specialized in cancer were more likely to answer questions appropriately (P = .02). Around half (39/84) of the physicians incorrectly defined a variant of uncertain significance (VUS). Over 75% made a recommendation for genetic testing that was not warranted. Many physicians have never received formal genetics training; however, they will be expected to provide an accurate explanation of the genetic test results and subsequent evidence-based medical management recommendations. These results demonstrate that a substantial proportion of physicians lack a true understanding of the implications a VUS. Utilization of supplemental genetics training programs coupled with increase awareness of genetic services may help to improve patient care.

A case of contralateral breast cancer and skin cancer associated with NBN heterozygous pathogenic variant c.698_701delAACA

Approximately 39.6% of people will be diagnosed with cancer during their lifetime. Several factors including, lifestyle, environment and genetics may play a role in its development. Understanding these causes will greatly improve treatment methods, prevention, and survival rates of these patients. Our patient, who has a positive family history of cancer, presented with contralateral breast cancer and multiple skin malignancies. Genetic testing revealed a frameshift variant in NBN. This gene encodes the protein, nibrin, which is involved in maintaining genomic stability. Several reports have identified heterozygous NBN frameshift (c.2028delT, c.2097dupT, c.657-661delACAAA) and splice site variants (c.1397+delG) in patients with breast cancer. However, our report is the first to describe a heterozygous c.698_701delAACA NBN variant in a patient with breast cancer. Since NBN is involved in DNA integrity, loss of functional protein due to pathogenic variants significantly increases the risk of various cancers. Given the family and personal history of our patient, in connection with previous reports of NBN pathogenic variants predisposition to cancer, this variant is predicted to be pathogenic and clinically significant.

Personalized molecular modeling for pinpointing associations of protein dysfunction and variants associated with hereditary cancer syndromes

Although the process of reclassification of a variant of uncertain significance can be complex, they are commonly detected through molecular testing. It often takes years before enough clinical data are acquired, and it can be costly and time‐consuming to perform functional analysis of a single variant. It is important that other tools are developed to aid in clarifying how a specific genetic variant impacts a proteins function, and ultimately the health of the patient.

The role of screening MRI in the era of next generation sequencing and moderate-risk genetic mutations

With the advent of next-generation sequencing, the ability to rapidly analyze numerous genes simultaneously has led to the creation of large cancer gene panels. Some of these genes, like BRCA1 and BRCA2, have been heavily researched and have well-established management guidelines. Other more newly established genes, like ATM, CHEK2, and PALB2, have previously had less robust research surrounding them which has limited the ability to create accurate risk estimates. With their inclusion on gene panels, there has been more pressure to produce management guidelines for patients discovered to carry pathogenic variants in these genes. For known high-risk genes, it is recommended for breast magnetic resonance imaging (MRI) and mammogram to be offered annually. This combination has been proven to be more effective at detecting breast cancer than mammography alone, with a combined sensitivity of 94% (Leach et al. in Lancet 365(9473):1769–1778, 2005). Women with a lifetime risk of breast cancer of 20% and higher have been recommended to have both breast MRI and mammography performed (Saslow et al. in CA Cancer J Clin 57(2):75–89, 2007). For women with pathogenic variants detected in moderate risk genes with lifetime breast cancer risks of at least 20%, breast MRI should be offered as part of their management. For more newly discovered genes with suspected associated risks at or above 20%, the use of breast MRI should be considered for their management as well.

Expanded phenotype in a patient with spastic paraplegia 7

Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG7.