Identification of pathogenic genetic variants in patients with acquired early-onset bilateral cataracts using next-generation sequencing.

BACKGROUND: Acquired early-onset bilateral cataracts can result from systemic etiologies or genetic disorders. METHODS: In this observational study, we analyzed individuals 18 months to 35 years of age with acquired bilateral cataracts via a next-generation sequencing panel of 66 genes to identify disease-causing genetic variants. RESULTS: Of 347 patients enrolled, 313 (90.2%) were <19 years (median, 8 years). We identified 74 pathogenic or likely pathogenic variants in 69 patients. Of the variants, we observed 64 single nucleotide variants (SNV) in 24 genes and 10 copy number variants (CNV) of varying size and genomic location. SNVs in crystallin genes were most common, accounting for 27.0% of all variants (20 of 74). Of those, recurrent variants included known cataract-causing variants CRYBA1 c.215+1G>A, observed in 3 patients, and CRYBA1 c.272_274delGAG, CRYBB2 c.463C>T and c.562C>T, and CRYAA c.62G>A, each observed in 2 patients. In 5 patients, we identified CNV deletions ranging from 1.32-2.41 Mb in size associated with 1q21.1 microdeletion syndrome. Biallelic variants in CYP27A1 were identified in two siblings, one as part of targeted follow-up family testing, who were subsequently diagnosed with cerebrotendinous xanthomatosis, a rare but treatable autosomal recessive disease that often presents with acquired early-onset bilateral cataracts. CONCLUSIONS: This study demonstrates the utility of genetic testing in individuals with acquired early-onset bilateral cataracts to help clarify etiology. Identification of causative genetic variants can inform patient management and facilitate genetic counseling by identifying genetic conditions with risk of recurrence in families.

Public Health Genetics: Surveying Preparedness for the Next Generation of Public Health Professionals.

Since the Human Genome Project's completion in 2003, the need for increased population genetic literacy has grown exponentially. To address this need, public health professionals must be educated appropriately to serve the public best. This study examines the current state of public health genetics education within existing master of public health (MPH) programs. A total of 171 MPH Council on Education for Public Health Accreditation (CEPH)-accredited programs across the nation were identified via a preliminary internet search. The American Public Health Association (APHA) Genomics Forum Policy Committee created 14 survey questions to assess the current status of incorporating genetics/genomics education within MPH programs. Using the Qualtrics survey system through the University of Pittsburgh, a link to the anonymous survey was sent to each director's email address obtained from their program's website. There were 41 survey responses, with 37 finished to completion, for a response rate of 21.6% (37/171). A total of 75.7% (28/37) of respondents reported having courses containing genetics/genomics information in their programs' coursework. Only 12.6% reported such coursework to be required for program completion. Commonly listed barriers to incorporating genetics/genomics include limited faculty knowledge and lack of space in existing courses and programs. Survey results revealed the incongruous and limited incorporation of genetics/genomics within the context of graduate-level public health education. While most recorded programs report offering public health genetics coursework, the extent and requirement of such instruction are not considered necessary for program completion, thereby potentially limiting the genetic literacy of the current pool of public health professionals.

Accurate 24-h urine cystine quantification for patients on cystine-binding thiol drugs.

Cystinuria is a rare disorder resulting in development of recurrent kidney stones, adversely affecting patient quality of life. The goal of cystinuria management is to reduce stone formation by increasing cystine solubility in urine, which includes lowering the urinary cystine level below its solubility limit. Treatment usually involves alkalinization of the urine and often requires initiating pharmacotherapy with a cystine-binding thiol drug (CBTD) such as tiopronin; however, proper dose adjustment requires accurate measurement of urinary cystine. The goal of this study was to validate a novel high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for quantification of cystine in the urine of patients with cystinuria receiving a CBTD. Urine samples were collected over 24 h from 24 patients and separated into 2 aliquots. Chromatographic separation of samples was conducted and separation of cystine from the cysteine-tiopronin drug complex was complete in < 3 min. The method was validated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantification (LOQ). Mean accuracy range was 97.7-102.3%; intermediate precision was high with relative percent difference values calculated at 1.2-9.3%; the calibration curve resulted in a linear response throughout the concentration range (R2 = 0.998); and the LOD and LOQ were 0.002 and 0.005 mg/mL, respectively. Mean (range) cystine concentrations measured were 111.10 (51.31-179.46) and 242.21 (61.14-741.80) g/L in Aliquots A and B, respectively. The HPLC-MS/MS method presented here indicates that urine cystine can be reliably quantified in patients receiving a CBTD.

Are We Prepared for Precision Public Health? An Examination of Genomics Content in Graduate Public Health Programs.

OBJECTIVE: With the completion of the Human Genome Project and swift development of genomic technologies, public health practitioners can use these advancements to more precisely target disease interventions to populations at risk. To integrate these innovations into better health outcomes, public health professionals need to have at least a basic understanding of genomics within various disciplines of public health. This descriptive study focused on the current level of genomics content in accredited master of public health (MPH) programs in the United States. METHODS: We conducted an internet search on all 171 Council on Education for Public Health (CEPH)-accredited MPH programs in the United States for genomics content in required and elective courses using the search terms "genetics," "genomics," and "molecular." RESULTS: Of the 171 CEPH-accredited MPH programs examined, 52 (30.4%) schools and programs in 34 states offered some type of genomics education. Thirty-five (20.5%) schools and programs had a course in genetic epidemiology, 29 (16.9%) had a course in genetic biostatistics or bioinformatics, and 17 (9.9%) had a course in general public health genomics. The remaining 119 offered no course with a focus on genetics or genomics. In addition, some electives or specifically focused courses related to genomics were offered. CONCLUSION: We found inadequate training in public health genomics for MPH students. To realize the promise of precision public health and to increase the understanding of genomics among the public health workforce, MPH programs need to find ways to integrate genomics education into their curricula.

Cancer genetic testing in marginalized groups during an era of evolving healthcare reform.

BACKGROUND: The Affordable Care Act and subsequent reforms pose tradeoffs for racial-ethnic, rural, and sex-related groups in the United States experiencing disparities in BRCA1/2 genetic counseling and testing and colorectal cancer screening, calling for policy changes. METHODS: A working group of the American Public Health Association Genomics Forum Policy Committee engaged in monthly meetings to examine ongoing literature and identify policy alternatives in the coverage of cancer genetic services for marginalized groups. 589 items were collected; 408 examined. Efforts continued from February 2015 through September 2020. RESULTS: African Americans and Latinos have shown 7-8 % drops in uninsured rates since the Exchanges opened. The ACA has increased BRCA1/2 test availability while several disparities remain, including by sex. Rural testing and screening utilization rates have improved. Medicaid expansion and the inclusion of Medicare in the ACA have resulted in mixed improvements in colorectal cancer screening rates in marginalized groups. CONCLUSION: Cancer genetic testing and screening to date have only partially benefited from healthcare reforms. Sensitivity to cost concerns and further monitoring of emerging data are needed. A reduction in disparities depends on the availability of private insurance, Medicaid and Medicare to the marginalized. Attention to value-based design and the way cancer benefits are translated into actual testing and screening are crucial. POLICY SUMMARY: The findings suggest the need for further benefits-related health agency interpretation of and amendments to the ACA, continued Medicaid and innovative Medicare expansion, and incorporation of cancer services values-based considerations at several levels, aimed at reducing group disparities.

The Effects of Inflammation on Alpha 1 Antitrypsin Levels in a National Screening Cohort.

Alpha 1 Antitrypsin (AAT) is a highly polymorphic serum protein. Several genetic variants are associated with varying degrees of decreased serum levels; however, these levels can rise in response to infection, inflammation, injury and estrogen levels. Although the effect of inflammation is well established, it has never been studied quantitatively with respect to specific genotypes in a large representative sample. Using data from a national AAT deficiency-targeted screening cohort, we evaluated AAT levels of patients with normal and deficiency genotypes in response to inflammation, indicated by elevated serum C-reactive protein (CRP). Additionally, we utilized a regression analysis to adjust for the effect of inflammation for each genotype. Across all stratified genotype groups, increased AAT levels were observed in patients with CRP ≥5 mg/L. Different AAT phenotypes reacted differently in the acute phase; M showed a strong response and Z a reduced reaction. Nevertheless, we discovered that inflammation significantly masked clinically relevant base AAT levels in some PI*MZ individuals; approximately a quarter of PI*MZ samples showed signs of inflammation. Median AAT levels (mg/dL) in the presence of inflammation are given for several genotypes; numbers in parentheses are levels from the cohort without inflammation/adjusted levels from the cohort with inflammation using the newly devised algorithm: PI*MM: 162 (142/140); PI*MS: 136 (117/115); PI*MZ: 104 (85/89); PI*MF: 161 (132/141); PI*SS: 115 (96/91); PI*SZ: 66 (54/50). We conclude that simultaneous determinations of CRP and AAT levels, and genotyping are clinically valuable in defining AAT variants and that the effect of inflammation can be adjusted for.