Results of an American College of Radiology-Society of Interventional Radiology Membership Survey on Exclusive Contracts and the Attitudes of Interventional Radiologists.

PURPOSE: To assess the attitudes of interventional radiologists (IRs) and diagnostic radiologists (DRs) toward exclusive contracts and independently practicing IRs who may request privileges at a hospital where an exclusive contract exists with a different group of radiologists. MATERIALS AND METHODS: A total of 22,400 survey instruments were distributed to 4,490 IRs and 17,910 DRs in the United States. Statistical evaluation included multivariate ordinal logistic regression analysis with calculation of the odds ratios and forest plots. RESULTS: Completed surveys were received from 525 (11.69%) IRs and 401 (2.23%) DRs. Given the low response rate of DRs, data analysis was focused on IRs. Early-career IRs and those in outpatient practices had a more positive attitude toward independent IRs who requested admitting and/or procedural privileges. A supermajority of both IRs and DRs who responded to the survey agreed that the importance of IR to hospital and health system contracts will increase. CONCLUSIONS: This survey identified many interrelated and complex variables that significantly affected the attitudes of IRs in various practice settings toward independent IRs requesting hospital admitting and/or procedural privileges. It will benefit independent IRs seeking admitting privileges to better understand some of the factors that impact the potential willingness of the radiology groups and other IRs with exclusive hospital contracts to work toward mutually beneficial practice paradigms, especially as more clinically oriented IRs complete their training in the new, integrated residency programs.

Interpretations of Examinations Outside of Radiologists' Fellowship Training: Assessment of Discrepancy Rates Among 5.9 Million Examinations From a National Teleradiology Databank.

BACKGROUND. In community settings, radiologists commonly function as multispecialty radiologists, interpreting examinations outside of their area of fellowship training. OBJECTIVE. The purpose of this article was to compare discrepancy rates for preliminary interpretations of acute community-setting examinations that are concordant versus discordant with interpreting radiologists' area of fellowship training. METHODS. This retrospective study used the databank of a U.S. teleradiology company that provides preliminary interpretations for client community hospitals. The analysis included 5,883,980 acute examinations performed from 2012 to 2016 that were preliminarily interpreted by 269 teleradiologists with a fellowship of neuroradiology, abdominal radiology, or musculoskeletal radiology. When providing final interpretations, client on-site radiologists voluntarily submitted quality assurance (QA) requests if preliminary and final interpretations were discrepant; the teleradiology company's QA committee categorized discrepancies as major (n = 8444) or minor (n = 17,208). Associations among examination type (common vs advanced), relationship between examination subspecialty and the teleradiologist's fellowship (concordant vs discordant), and major and minor discrepancies were assessed using three-way conditional analyses with generalized estimating equations. RESULTS. For examinations with a concordant subspecialty, the major discrepancy rate was lower for common than for advanced examinations (0.13% vs 0.26%; relative risk [RR], 0.50, 95% CI, 0.42-0.60; p < .001). For examinations with a discordant subspecialty, the major discrepancy rate was lower for common than advanced examinations (0.14% vs 0.18%; RR, 0.81; 95% CI, 0.72-0.90; p < .001). For common examinations, the major discrepancy rate was not different between examinations with concordant versus discordant subspecialty (0.13% vs 0.14%; RR, 0.90; 95% CI, 0.81-1.01; p = .07). For advanced examinations, the major discrepancy rate was higher for examinations with concordant versus discordant subspecialty (0.26% vs 0.18%; RR, 1.45; 95% CI, 1.18-1.79; p < .001). The minor discrepancy rate was higher among advanced examinations for those with concordant versus discordant subspecialty (0.34% vs 0.29%; RR, 1.17; 95% CI, 1.00-1.36; p = .04), but not different for other comparisons (p > .05). CONCLUSION. Major and minor discrepancy rates were not higher for acute community-setting examinations outside of interpreting radiologists' fellowship training. Discrepancy rates increased for advanced examinations. CLINICAL IMPACT. The findings support multispecialty radiologist practice in acute community settings. Efforts to match examination and interpreting radiologist sub-specialty may not reduce diagnostic discrepancies.

Disparities in the Use of Emergency Department Advanced Imaging in Medicare Beneficiaries.

OBJECTIVE. The purpose of our study was to assess potential disparities in the utilization of advanced imaging during emergency department (ED) visits. MATERIALS AND METHODS. This retrospective study was conducting using 5% Research Identifiable Files. All CT and MRI (together defined as "advanced imaging") examinations associated with ED visits in 2015 were identified for continuously enrolled Medicare beneficiaries. Individuals with medical claims 30 days before the index ED event were excluded, and encounters that occurred in hospitals without advanced imaging capabilities were also excluded. Patient characteristics were identified using Medicare files and hospital characteristics using the American Hospital Association Annual Survey of Hospitals. Multivariate logistic regression was used for the analysis. RESULTS. Of 86,976 qualifying ED encounters, 52,833 (60.74%) ED encounters were for female patients; 29.03% (n = 25,245) occurred at rural hospitals and 15.81% (n = 13,750) at critical access hospitals. Race distribution was 83.13% White, 11.05% Black, and 5.82% Other. Compared with ED patients at urban hospitals, those at rural and critical access hospitals were 6.9% less likely (odds ratio [OR] = 0.931, p = 0.015) and 18.0% less likely (OR = 0.820, p < 0.0001), respectively, to undergo advanced imaging. Compared with White patients, Black patients were 31.6% less likely (OR = 0.684, p < 0.0001) to undergo advanced imaging. Relative to their urban counterparts, both White (OR = 0.941, p = 0.05) and Black (OR = 0.808, p = 0.047) rural ED patients were less likely to undergo advanced imaging. CONCLUSION. Among Medicare beneficiaries receiving care in U.S. EDs, significant disparities exist in advanced imaging utilization. Although imaging appropriateness was not investigated, these findings suggest inequity. Further research is necessary to understand why consistent health benefits do not translate into consistent imaging access among risk-adjusted ED patients.

Impact of variant reclassification in the clinical setting of cardiovascular genetics.

Genetic testing for cardiovascular disease (CVD) has advanced over the past ten years, but these advancements have posed new challenges in variant classification. To address these challenges, ACMG/AMP published guidelines for variant interpretation in 2015. This study aimed to determine what impact these guidelines have on variant classification in clinical cardiovascular genetics. A retrospective chart review identified patients who underwent clinical genetic testing and had a variant identified in a gene associated with CVD. For each variant, systematic evidence review was performed and ACMG guidelines were applied for classification. These classifications were compared to those provided on patients' genetic test reports. This study identified 223 unique variants in 237 patients. Seventy-nine (35%) of the variants had classifications that differed from their clinical reports. Twenty-eight (35%) of these reclassifications would have changed medical management recommendations for 38 patients. Application of these guidelines resulted in reclassification for approximately one-third of the variants in this study. Clinicians can have a more active role in the process of variant classification. Variant classifications should be updated over time in the clinical CVD setting due to the impact reclassifications can have on clinical screening recommendations.

Emerging Challenges and Opportunities in the Evolution of Teleradiology.

OBJECTIVE. In recent decades, teleradiology has expanded considerably, and many radiology practices now engage in intraorganizational or extraorganizational teleradiology. In this era of patient primacy, optimizing patient care and care delivery is paramount. This article provides an update on recent changes, current challenges, and future opportunities centered around the ability of teleradiology to improve temporal and geographic imaging access. We review licensing and regulations and discuss teleradiology in providing services to rural areas and assisting with disaster response, including the response to the coronavirus disease (COVID-19) pandemic. CONCLUSION. Teleradiology can help increase imaging efficiency and mitigate both geographic and temporal discrepancies in imaging care. Technologic limitations and regulatory hurdles hinder the optimal practice of teleradiology, and future attention to these issues may help ensure broader patient access to high-quality imaging across the United States.

Understanding BRCA Mutation Carriers' Preferences for Communication of Genetic Modifiers of Breast Cancer Risk.

Refined estimates of risk based on genetic risk modifiers could assist BRCA mutation carriers in understanding their risk, but it is not clear whether carriers are interested in receiving these estimates or how they might benefit from them. Using qualitative interviews, we investigated female BRCA1 and BRCA2 mutation carriers' (N = 20) reactions to numerical and verbal presentations of breast cancer risk based on risk modifiers and assessed women's preferences regarding visual formats for communicating risk. Our results show carriers are interested in receiving refined risk estimates and suggest the estimates may influence decision-making regarding cancer prevention, depending on the nature of the risk assessment. Although accurate and precise estimates of breast cancer risk are most important to women, they preferred quantitative risk estimates expressed as a proportion with or without a population comparison; however, women noted that comparisons to other BRCA mutation carriers were less useful given their high risk. Participants also preferred communication of a risk as a specific percentage versus a range of risk, but a clear preference regarding visual displays was not expressed. Results support many existing recommendations for genetic risk communication and provide guidance for the development of tools incorporating genetic risk modifiers.

Assessing the Clinical Utility of SNP Microarray for Prader-Willi Syndrome due to Uniparental Disomy.

Maternal uniparental disomy (UPD) 15 is one of the molecular causes of Prader-Willi syndrome (PWS), a multisystem disorder which presents with neonatal hypotonia and feeding difficulty. Current diagnostic algorithms differ regarding the use of SNP microarray to detect PWS. We retrospectively examined the frequency with which SNP microarray could identify regions of homozygosity (ROH) in patients with PWS. We determined that 7/12 (58%) patients with previously confirmed PWS by methylation analysis and microsatellite-positive UPD studies had ROH (>10 Mb) by SNP microarray. Additional assessment of 5,000 clinical microarrays, performed from 2013 to present, determined that only a single case of ROH for chromosome 15 was not caused by an imprinting disorder or identity by descent. We observed that ROH for chromosome 15 is rarely incidental and strongly associated with hypotonic infants having features of PWS. Although UPD microsatellite studies remain essential to definitively establish the presence of UPD, SNP microarray has important utility in the timely diagnostic algorithm for PWS.

Partial tetrasomy 11q resulting from an intrachromosomal triplication of a 22 Mb region of chromosome 11.

Intrachromosomal triplications are complex chromosomal rearrangements which arise during meiosis or mitosis and lead to a tetrasomic dose of the affected genomic regions. We describe a female patient harboring an intrachromosomal triplication who presented to the Genetics clinic with dysmorphic features, including telecanthus, flat facial profile, and prognathism, short stature, widely spaced nipples, multiple allergy complaints, loose bowel movements, and mild speech delay. Microarray analysis showed a copy number gain of a 22.37 Mb region of chromosome 11 between bands 11q14.1 and 11q22.1. This region contains 95 genes and seven microRNAs, none of which have been implicated in a disease resulting from increased gene dosage. FISH analysis using a probe targeted to the middle of the segment of the copy number gain yielded a pattern indicative of a tetrasomy via an intrachromosomal triplication, with three signals on the long arm of one homologue of chromosome 11 and the fourth on the other homologue. Subsequent FISH analysis showed that the middle triplicated fragment was positioned in an inverted orientation relative to the outer fragments. To investigate the mechanism by which the intrachromosomal triplication occurred, SNP microarray analysis was performed. These results were consistent with the presence of multiple haplotypes in the tetrasomic region and suggest that the intrachromosomal triplication in our patient arose in one parent during meiosis. © 2017 Wiley Periodicals, Inc.

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder.

Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.

Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities.

Segmental duplications, which comprise approximately 5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are approximately 2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is approximately 2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.

Duplication of the Xq27.3-q28 region, including the FMR1 gene, in an X-linked hypogonadism, gynecomastia, intellectual disability, short stature, and obesity syndrome.

In 1979 a "new" syndrome characterized by X-linked inheritance, hypogonadism, gynecomastia, intellectual disability, obesity, and short stature was described. The now-36-year-old propositus was recently referred to the genetics clinic for profound intellectual disability. Fragile X testing initially demonstrated a duplication of the FMR1 region, and upon further testing we identified an Xq27.3-q28 8.05 Mb-long duplication responsible for a syndrome. Our report describes the molecular and clinical aspects of the X-linked syndrome. Our results suggest that male patients with intellectual disability, hypogonadism, short stature, and gynecomastia should be further investigated for rearrangements in the Xq27.3-q28 region. In the future, when more cases of the duplication are identified, it may become possible to more accurately determine the specific genes affected by overexpression and responsible for the phenotype.

12q14 microdeletion associated with HMGA2 gene disruption and growth restriction.

The 12q14 microdeletion syndrome is a rare condition that has previously been characterized by pre- and postnatal growth restriction, proportionate short stature, failure to thrive, developmental delay, and osteopoikilosis. Previously reported microdeletions within this region have ranged in size from 1.83 to 10.12 Mb with a proposed 2.61 Mb smallest region of overlap containing the LEMD3, HMGA2, and GRIP1 genes. Here, we report on the identification of a 12q14 microdeletion in a female child presenting with proportionate short stature, failure to thrive, and speech delay. The genomic loss (minimum size 4.17 Mb, maximum size 4.21 Mb) contained 25 RefSeq genes including IRAK3, GRIP1, and the 3' portion of the HMGA2 gene. This is the first partial deletion of HMGA2 associated with the 12q14 microdeletion syndrome. This case further clarifies the association of LEMD3 deletions with the 12q14 microdeletion syndrome and provides additional support for the role of the HMGA2 gene in human growth.

Microarray comparative genomic hybridization and cytogenetic characterization of tissue-specific mosaicism in three patients.

The presence of more than one cell line in an individual may often be missed by classical cytogenetic analysis due to a low percentage of affected cells or analysis of cells from an unaffected or less affected germ layer. Array comparative genomic hybridization (aCGH) from whole blood or tissue is an important adjunct to standard karyotyping due to its ability to detect genomic imbalances that are below the resolution of karyotype analysis. We report results from three unrelated patients in whom aCGH revealed mosaicism not identified by peripheral blood chromosome analysis. This study further illustrates the important application of aCGH in detecting tissue-specific mosaicism, thereby leading to an improvement in the ability to provide a diagnosis for patients with normal chromosome analysis and dysmorphic features, congenital anomalies, and/or developmental delay.

Locoregional MYCN-amplified neuroblastoma.

MYCN-amplification is strongly associated with other high-risk prognostic factors and poor outcome in neuroblastoma. Infrequently, amplification of MYCN has been identified in localized tumors with favorable biologic features. Outcome for these children is difficult to predict and optimal treatment strategies remain unclear. We report a 5-month-old who presented with an MYCN-amplified INSS stage 3, pelvic neuroblastoma. The tumor had favorable histology, hyperdiploidy, and lacked 1p36 and 11q23 aberrations. Although the patient met the criteria for high-risk neuroblastoma, because of the discordant prognostic markers we elected to treat her according to an intermediate-risk protocol. She remains event-free more than 18 months.

What's in a Name? Report of the ACR Task Force on General Radiology and Multi-Subspecialization.

The ACR Council passed Resolution 47 at its 2020 annual meeting establishing a representative task force (TF) to explore the concept of the "multispecialty radiologist," previously proposed in 2012. The TF held eight virtual meetings over 8 months, considered data from a 2020 ACR Membership Tracking Survey, conducted a review of current literature, and collected anecdotal experience from TF members and ACR leadership. ACR legal counsel and a cross-section of ACR Commissions and Committees also provided input. The TF concluded that there is scant interest from the radiology community in the multispecialty radiologist title and no agreed-upon definition for the term. Radiologists may identify as diagnostic or subspecialty radiologists; however, the roles they fill in clinical practice include general, multispecialty, and subspecialized radiology. The TF proposes definitions for each of these terms to support radiologist recruitment aligned with optimal patient care in the practice community and to improve the quality of data collection about the field. To reduce ambiguity, the TF proposes adoption of the defined terms by the radiology community, including radiologist recruiters and employers, and suggests ways in which resident training and the ABR board examination can be adapted to support this new structure. Additionally, as part of an exploration of hyperspecialization and trainee preparedness for clinical practice, the TF discussed the challenges faced by community-based practices seeking to provide a full range of high-quality, radiologist-delivered diagnostic and interventional services to their patient populations.

Establishing analytical validity of BeadChip array genotype data by comparison to whole-genome sequence and standard benchmark datasets.

BACKGROUND: Clinical use of genotype data requires high positive predictive value (PPV) and thorough understanding of the genotyping platform characteristics. BeadChip arrays, such as the Global Screening Array (GSA), potentially offer a high-throughput, low-cost clinical screen for known variants. We hypothesize that quality assessment and comparison to whole-genome sequence and benchmark data establish the analytical validity of GSA genotyping. METHODS: To test this hypothesis, we selected 263 samples from Coriell, generated GSA genotypes in triplicate, generated whole genome sequence (rWGS) genotypes, assessed the quality of each set of genotypes, and compared each set of genotypes to each other and to the 1000 Genomes Phase 3 (1KG) genotypes, a performance benchmark. For 59 genes (MAP59), we also performed theoretical and empirical evaluation of variants deemed medically actionable predispositions. RESULTS: Quality analyses detected sample contamination and increased assay failure along the chip margins. Comparison to benchmark data demonstrated that > 82% of the GSA assays had a PPV of 1. GSA assays targeting transitions, genomic regions of high complexity, and common variants performed better than those targeting transversions, regions of low complexity, and rare variants. Comparison of GSA data to rWGS and 1KG data showed > 99% performance across all measured parameters. Consistent with predictions from prior studies, the GSA detection of variation within the MAP59 genes was 3/261. CONCLUSION: We establish the analytical validity of GSA assays using quality analytics and comparison to benchmark and rWGS data. GSA assays meet the standards of a clinical screen although assays interrogating rare variants, transversions, and variants within low-complexity regions require careful evaluation.

Newborn and carrier screening for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. The homozygous absence of SMN1 exon 7 has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. Treatment and prevention of SMA are complementary responses to the challenges presented by SMA. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through accurate diagnosis and carrier and prenatal diagnosis is of the utmost importance. The goal of population-based SMA carrier screening is to identify couples at risk for having a child with SMA, thus allowing carriers to make informed reproductive choices. During this study we performed two pilot projects addressing the clinical applicability of testing in the newborn period and carrier screening in the general population. We have demonstrated that an effective technology does exist for newborn screening of SMA. We also provide an estimate of the carrier frequency among individuals who accepted carrier screening, and report on patient's knowledge and attitudes toward SMA testing.

Unexpected detection of dystrophin gene deletions by array comparative genomic hybridization.

Array comparative genomic hybridization has increasingly become the standard of care to evaluate patients for genomic imbalance. As the patient population evaluated by microarray expands, there is certain to be an increase in the detection of unexpected, yet common diseases. When array results predict a late-onset disorder or cancer predisposition, it becomes a challenge for physicians and counselors to adequately address with patients. Included in this study were three patients described with nonspecific phenotypic findings who underwent microarray testing to better define their disease etiology. An unexpected deletion within the dystrophin gene was observed in each case, despite that no patient was suspected of a dystrophinopathy at the time of testing. The patients included an 8-day-old male with a dystrophin deletion predictive of Becker muscular dystrophy, an 18-month old female found to be the carrier of deletion, and a 4-year-8-month-old male with a deletion predictive of Duchenne muscular dystrophy. In this circumstance it becomes difficult to counsel the family, as well as to predict disease course when underlying medical conditions may exist. However, early detection may enable the patient to receive proactive treatment, and allows for screening of at-risk family members. Ultimately, it is up to the clinician to promote informed decision-making within the family prior to testing, and ensure that adequate counseling is provided during follow-up.

Novel diagnostic features of dysferlinopathies.

Reports of dysferlinopathy have suggested a clinically heterogeneous group of patients. We identified specific novel molecular and phenotypic features that help distinguish dysferlinopathies from other forms of limb-girdle muscular dystrophy (LGMD). A detailed history, physical exam, and protein and mutation analysis of genomic DNA was done for all subjects. Five of 21 confirmed DYSF gene mutations were not previously reported. A distinct "bulge" of the deltoid muscle in combination with other findings was a striking feature in all patients. Six subjects had atypical calf enlargement, and 3 of these exhibited a paradoxical pattern of dysferlin expression: severely reduced by direct immunofluorescence with overexpression on Western blots. Six patients showed amyloid deposits in muscle that extended these findings to new domains of the dysferlin gene, including the C2G domain. Correlative studies showed colocalization of amyloid with deposition of dysferlin. The present data further serve to guide clinicians facing the expensive task of molecular characterization of patients with an LGMD phenotype.