Publications by authors named "Leslie G Biesecker"

294 Publications

Case Report: Five-Year Experience of AKT Inhibition with Miransertib (MK-7075) in an Individual with Proteus Syndrome.

Cold Spring Harb Mol Case Stud 2021 Oct 14. Epub 2021 Oct 14.

National Institutes of Health.

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the five-year follow up of an 18-year-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-week phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. He has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to five years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. While an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.
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http://dx.doi.org/10.1101/mcs.a006134DOI Listing
October 2021

The role of future-oriented affect in engagement with genomic testing results.

J Behav Med 2021 Sep 4. Epub 2021 Sep 4.

Basic Biobehavioral and Psychological Sciences Branch, Behavioral Research Program, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, #3E-216, Bethesda, MD, USA.

Future-oriented emotions such as anticipatory affect (i.e., current affect experienced regarding a potential future outcome) and anticipated affect (i.e., expectations about potential future affect), are uniquely associated with health decision-making (e.g., electing to receive results of genomic testing). This study investigated the degree to which negative anticipated and anticipatory emotions predict health decision making over time, and whether such emotions predict social, emotional, and behavioral responses to anticipated information (e.g., genomic testing results). 461 participants (M age = 63.9, SD = 5.61, 46% female) in a genomic sequencing cohort who elected to receive genomic sequencing (carrier) results were included in the current study. Anticipated and anticipatory affect about sequencing results were assessed at baseline. Psychological and behavioral responses to sequencing results, including participants' reported anxiety, decisional conflict, and distress about sequencing results, whether they shared results with family members, and their intentions to continue learning results in the future, were collected immediately, one month, and/or six months after receiving results. More negative anticipated and anticipatory affect at baseline was significantly and independently associated with lower intentions to continue learning results in the future, as well as higher levels of anxiety and uncertainty at multiple time points after receiving results. Anticipated negative affect was also associated with greater decisional conflict, and anticipatory negative affect was also associated with greater distress after receiving results. Future-oriented emotions may play an important role in decisions that unfold over time, with implications for genomic testing, behavioral medicine, and health decision-making broadly.
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http://dx.doi.org/10.1007/s10865-021-00253-7DOI Listing
September 2021

A systematic literature review of disclosure practices and reported outcomes for medically actionable genomic secondary findings.

Genet Med 2021 Aug 26. Epub 2021 Aug 26.

Center for Precision Health Research, National Human Genome Research Institute, Bethesda, MD, USA.

Purpose: Secondary findings (SFs) are present in 1-4% of individuals undergoing genome/exome sequencing. A review of how SFs are disclosed and what outcomes result from their receipt is urgent and timely.

Methods: We conducted a systematic literature review of SF disclosure practices and outcomes after receipt including cascade testing, family and provider communication, and health-care actions. Of the 1,184 nonduplicate records screened we summarize findings from 27 included research articles describing SF disclosure practices, outcomes after receipt, or both.

Results: The included articles reported 709 unique SF index recipients/families. Referrals and/or recommendations were provided 647 SF recipients and outcome data were available for 236. At least one recommended evaluation was reported for 146 SF recipients; 16 reports of treatment or prophylactic surgery were identified. We found substantial variations in how the constructs of interest were defined and described.

Conclusion: Variation in how SF disclosure and outcomes were described limited our ability to compare findings. We conclude the literature provided limited insight into how the American College of Medical Genetics and Genomics (ACMG) guidelines have been translated into precision health outcomes for SF recipients. Robust studies of SF recipients are needed and should be prioritized for future research.
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http://dx.doi.org/10.1038/s41436-021-01295-7DOI Listing
August 2021

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

A standard of care for individuals with PIK3CA-related disorders: An international expert consensus statement.

Clin Genet 2021 Jul 8. Epub 2021 Jul 8.

Centre for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.
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http://dx.doi.org/10.1111/cge.14027DOI Listing
July 2021

Dermatologic findings in individuals with genetically confirmed Proteus syndrome.

Pediatr Dermatol 2021 Jul 8;38(4):794-799. Epub 2021 Jun 8.

Department of Dermatology, Uniformed Services University, Bethesda, MD, USA.

Background/objective: Proteus syndrome, caused by a mosaic activating AKT1 variant, typically presents in toddlers with progressive, asymmetric overgrowth of the skin and bones. We aimed to define the spectrum of dermatologic disease in individuals with genetically confirmed Proteus syndrome.

Methods: We conducted a retrospective review of records from dermatologic examinations of individuals evaluated at the NIH with a molecular diagnosis of Proteus syndrome. The types, prevalence, and localization of dermatologic findings were assessed.

Results: Fifty-one individuals (29 males, 22 females, mean age: 9 years) with clinical features of Proteus syndrome had the mosaic c.49G>A, p.Glu17Lys AKT1 variant. Fifty (98%) had at least one cutaneous feature constituting current clinical diagnostic criteria, including vascular malformations in 42 (82%), epidermal nevus in 41 (80%), volar cerebriform connective tissue nevi in 34 (67%), and adipose dysregulation in 30 (59%). Forty-nine (96%) had at least one dermatologic finding not included within the diagnostic criteria, including confluent volar skin-colored to hypopigmented papules or nodules (n = 33, 65%), papules or nodules on the digits or face (n = 27, 53%), and nonlinear epidermal nevi (n = 15, 29%). Other frequently observed features include nail changes (n = 28, 55%), hyperpigmented macules (n = 27, 53%), patchy dermal hypoplasia (n = 18, 35%), gingival/oral mucosal overgrowth (n = 17, 33%), hypopigmented macules (n = 16, 31%), dental enamel changes (n = 9, 18%), acrochordons (n = 6, 12%), and lingual overgrowth (n = 4, 8%).

Conclusions: The range of mucocutaneous features occurring in Proteus syndrome is broader than previously considered. These observations may assist in earlier diagnosis and management and provide novel insights regarding the pathogenesis of the condition.
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http://dx.doi.org/10.1111/pde.14624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403137PMC
July 2021

Ethical, legal and social implications of human genome studies in radiation research: a workshop report for studies on atomic bomb survivors at the Radiation Effects Research Foundation.

J Radiat Res 2021 Jul;62(4):656-661

Department of Social System Design, Eikei University of Hiroshima, Hiroshima 730-0016, Japan.

The Radiation Effects Research Foundation (RERF) is the primary organization in Japan dedicated to studying the health consequences of the Hiroshima and Nagasaki atomic bombings in World War II. In December 2020, RERF held a virtual international workshop on the ethical, legal and social implications (ELSI) of genome studies. In this workshop, the ELSI considerations of future human genome studies on radiation research including atomic bomb survivors and their families were discussed. Since genome sequencing (GS) is now practical and affordable, RERF now plans GS of parents/child trios to examine genetic effects of atomic bomb radiation. As such studies may engender some novel risks and benefits, ethics review and engagement with families (including consent) need to be considered. These include protection of individual privacy, use of samples from deceased prior participants, return of results to the participants, public sharing of genome data and advance science and social welfare. Specifically with regard to social welfare, the results of such studies may have implications for public and government decision-making regarding social benefits of victims and other important questions. Based on these broad-ranging discussions we have developed the following concepts to guide this work: "trust," "compromise" and "relationship building," inclusive of the concerned stakeholders, scientific aims and Japanese society at large. We conclude that in order to realize, establish and maintain these concepts, it is essential to put procedures into place to ensure the successful, consensus-based implementation of the RERF studies.
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http://dx.doi.org/10.1093/jrr/rrab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273803PMC
July 2021

Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth.

Genet Med 2021 10 26;23(10):1882-1888. Epub 2021 May 26.

University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.

Purpose: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1.

Methods: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity.

Results: The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone.

Conclusion: Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.
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http://dx.doi.org/10.1038/s41436-021-01211-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486672PMC
October 2021

Dyadic concordance and associations of beliefs with intentions to learn carrier results from genomic sequencing.

J Behav Med 2021 May 13. Epub 2021 May 13.

National Cancer Institute, Rockville, MD, USA.

Although romantic couple concordance has been demonstrated across a wide array of health behaviors, little research has examined dyadic concordance in health beliefs. This study examined the extent to which cohabitating romantic dyads' attitudes and beliefs coincide (i.e., dyadic concordance) in addition to how well they predict intentions to learn genomic sequencing results. The actor-partner interdependence model was applied to cross-sectional data from 81 dyads in an exome sequencing study who were surveyed about their risk perceptions, worry, information avoidance, attitudes, and intentions toward learning carrier results. Information avoidance tendencies were positively correlated between partners, but there was low concordance on other beliefs. Individuals' attitudes and information avoidance predicted their own intentions to learn results. Additionally, partners' information avoidance tendencies predicted their partner's intentions to learn results. Future research should explore mechanisms through which one's partner's information avoidance may affect one's own intentions and behaviors.
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http://dx.doi.org/10.1007/s10865-021-00222-0DOI Listing
May 2021

Engagement and return of results preferences among a primarily African American genomic sequencing research cohort.

Am J Hum Genet 2021 05 21;108(5):894-902. Epub 2021 Apr 21.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.

Genomics researchers are increasingly interested in what constitutes effective engagement of individuals from underrepresented groups. This is critical for longitudinal projects needed to inform the implementation of precision medicine. Return of results is one opportunity for engagement. The aims of this study were to determine participant perspectives on optimal engagement strategies and priorities for return of results and the extent to which focus groups were an effective modality for gathering input on these topics. We conducted six professionally moderated focus groups with 49 participants in a genomics research study. Transcripts from audio-recorded sessions were coded by two researchers and themes were discussed with the wider research team. All groups raised the issue of mistrust. Individuals participated nonetheless to contribute their perspectives and benefit their community. Many group members preferred engagement modalities that are offered to all participants and allow them to share the nuances of their perspectives over the use of participant representatives and surveys. All groups created a consensus ranking for result return priorities. Results for life-threatening conditions were the highest priority to return, followed by those related to treatable conditions that affect physical or mental health. We advocate for engagement strategies that reach as many participants as possible and allow them to share their perspectives in detail. Such strategies are valued by participants, can be effective for developing return of results policies, and may help institutions become more trustworthy.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206196PMC
May 2021

Preferences for and acceptability of receiving pharmacogenomic results by mail: A focus group study with a primarily African-American cohort.

J Genet Couns 2021 Apr 19. Epub 2021 Apr 19.

University of Technology Sydney, Sydney, Australia.

Although genetic counseling is traditionally done through in-person, one-on-one visits, workforce shortages call for efficient result return mechanisms. Studies have shown that telephone and in-person return of cancer genetic results are equivalent for patient outcomes. Few studies have been conducted with other modes, result types or racially diverse participants. This study explored participants' perspectives on receiving pharmacogenomic results by mail. Two experienced moderators facilitated six focus groups with 49 individuals who self-identified primarily as African-American and consented to participate in a genome sequencing cohort study. Participants were given a hypothetical pharmacogenomic result report (positive for c.521T>C in SLCO1B1). An accompanying letter explained that the result was associated with statin intolerance along with a recommendation to share it with one's doctor and immediate relatives. Participants reacted to the idea of receiving this type of result by mail, discussing whether the letter's information was sufficient and what they predicted they would do with the result. Two researchers coded the focus group transcripts and identified themes. Many participants thought that it was appropriate to receive the result through the mail, but some suggested a phone call alerting the recipient to the letter. Others emphasized that although a letter was acceptable for disclosing pharmacogenomic results, it would be insufficient for what they perceived as life-threatening results. Most participants found the content sufficient. Some participants suggested resources about statin intolerance and warning signs be added. Most claimed they would share the result with their doctor, yet few participants offered they would share the result with their relatives. This exploratory study advances the evidence that African-American research participants are receptive to return of certain genetic results by approaches that do not involve direct contact with a genetic counselor and intend to share results with providers. ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study (NCT00410241).
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http://dx.doi.org/10.1002/jgc4.1424DOI Listing
April 2021

Low-level variant calling for non-matched samples using a position-based and nucleotide-specific approach.

BMC Bioinformatics 2021 Apr 8;22(1):181. Epub 2021 Apr 8.

National Human Genome Research Institute, National Institutes of Health, 50 South Drive Room 5140, Bethesda, MD, 20892, USA.

Background: The widespread use of next-generation sequencing has identified an important role for somatic mosaicism in many diseases. However, detecting low-level mosaic variants from next-generation sequencing data remains challenging.

Results: Here, we present a method for Position-Based Variant Identification (PBVI) that uses empirically-derived distributions of alternate nucleotides from a control dataset. We modeled this approach on 11 segmental overgrowth genes. We show that this method improves detection of single nucleotide mosaic variants of 0.01-0.05 variant allele fraction compared to other low-level variant callers. At depths of 600 × and 1200 ×, we observed > 85% and > 95% sensitivity, respectively. In a cohort of 26 individuals with somatic overgrowth disorders PBVI showed improved signal to noise, identifying pathogenic variants in 17 individuals.

Conclusion: PBVI can facilitate identification of low-level mosaic variants thus increasing the utility of next-generation sequencing data for research and diagnostic purposes.
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http://dx.doi.org/10.1186/s12859-021-04090-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028235PMC
April 2021

Correspondence on: "Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features".

Atherosclerosis 2021 06 20;326:63-64. Epub 2021 Mar 20.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive 5140, Bethesda, MD, 20892, USA. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.015DOI Listing
June 2021

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility.

Genet Med 2021 07 25;23(7):1288-1295. Epub 2021 Mar 25.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH).

Methods: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.

Results: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance.

Conclusion: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.
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http://dx.doi.org/10.1038/s41436-021-01125-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263483PMC
July 2021

Cardiothoracic imaging findings of Proteus syndrome.

Sci Rep 2021 03 22;11(1):6577. Epub 2021 Mar 22.

Cardiovascular and Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, Building 10, Room B1D416, 10 Center Drive, Bethesda, MD, 20814, USA.

In this work, we sought to delineate the prevalence of cardiothoracic imaging findings of Proteus syndrome in a large cohort at our institution. Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging (routine chest CT, CT pulmonary angiography and/or cardiac MRI). All studies were retrospectively and independently reviewed by two fellowship-trained cardiothoracic readers. Disagreements were resolved by consensus. Differences between variables were analyzed via parametric and nonparametric tests based on the normality of the distribution. The cardiothoracic findings of Proteus syndrome were diverse, but several were much more common and included: scoliosis from bony overgrowth (94%), pulmonary venous dilation (62%), band-like areas of lung scarring (56%), and hyperlucent lung parenchyma (50%). In addition, of 20 individuals who underwent cardiac MRI, 9/20 (45%) had intramyocardial fat, mostly involving the endocardial surface of the left ventricular septal wall. There was no statistically significant difference among the functional cardiac parameters between individuals with and without intramyocardial fat. Only one individual with intramyocardial fat had mildly decreased function (LVEF = 53%), while all others had normal ejection fraction.
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http://dx.doi.org/10.1038/s41598-021-86029-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985501PMC
March 2021

Clinical diagnosis of presumed SOX2 gonadosomatic mosaicism.

Ophthalmic Genet 2021 06 15;42(3):320-325. Epub 2021 Mar 15.

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.

: To describe a family with presumed gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the gene was confirmed in the proband by Sanger sequencing.: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.
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http://dx.doi.org/10.1080/13816810.2021.1888127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154737PMC
June 2021

SomatoSim: precision simulation of somatic single nucleotide variants.

BMC Bioinformatics 2021 Mar 6;22(1):109. Epub 2021 Mar 6.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Somatic single nucleotide variants have gained increased attention because of their role in cancer development and the widespread use of high-throughput sequencing techniques. The necessity to accurately identify these variants in sequencing data has led to a proliferation of somatic variant calling tools. Additionally, the use of simulated data to assess the performance of these tools has become common practice, as there is no gold standard dataset for benchmarking performance. However, many existing somatic variant simulation tools are limited because they rely on generating entirely synthetic reads derived from a reference genome or because they do not allow for the precise customizability that would enable a more focused understanding of single nucleotide variant calling performance.

Results: SomatoSim is a tool that lets users simulate somatic single nucleotide variants in sequence alignment map (SAM/BAM) files with full control of the specific variant positions, number of variants, variant allele fractions, depth of coverage, read quality, and base quality, among other parameters. SomatoSim accomplishes this through a three-stage process: variant selection, where candidate positions are selected for simulation, variant simulation, where reads are selected and mutated, and variant evaluation, where SomatoSim summarizes the simulation results.

Conclusions: SomatoSim is a user-friendly tool that offers a high level of customizability for simulating somatic single nucleotide variants. SomatoSim is available at https://github.com/BieseckerLab/SomatoSim .
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http://dx.doi.org/10.1186/s12859-021-04024-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936459PMC
March 2021

Adaptation of the working alliance inventory for the assessment of the therapeutic alliance in genetic counseling.

J Genet Couns 2021 02 7;30(1):11-21. Epub 2021 Feb 7.

Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

The concept of therapeutic alliance is central to genetic counseling as the mechanism through which the outcomes of empowerment and effective coping are likely to be achieved. To date, there have been no published systematic assessments of the therapeutic relationship in genetic counseling. We adapted a previously validated measure of the therapeutic alliance to genetic counseling and assessed its reliability and validity. Participants were enrolled in a clinical genomic study where they were randomized to receive education about carrier results via a Web platform or via a genetic counselor and then further randomized to receive genetic counseling (without additional education) or not. We rated the therapeutic alliance from audio recordings of 120 genetic counseling sessions. We modified the observer version of the Working Alliance Inventory (WAI-O), initially designed to assess therapeutic relationships in psychotherapy. We examined internal consistency reliability by calculating Cronbach's alpha and inter-rater reliability through both percent agreement and Gwet's alternative agreement coefficient (AC). Regression analyses were used to evaluate the relationship of WAI-O scores with session length and with the designation of the session as one in which prior education was delivered by the genetic counselor or not. The adapted scale had high-reliability characteristics with agreement of 88%-93%, Gwet's AC of 0.84-0.90, and Cronbach's alpha of 0.89-0.93 for the three WAI-O subscales (bonds, goals, and tasks). Although there was no difference in alliance based on whether prior education was provided by the genetic counselor, the total WAI-O score significantly increased with increasing session length (beta =0.667, p<.001), providing preliminary evidence of construct validity. The WAI-O that we have adapted can be used reliably with two independent raters to assess the therapeutic alliance in studies of genetic counseling. The initial evidence for construct validity is promising and should be reassessed in future genetic counseling studies using the WAI-O.
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http://dx.doi.org/10.1002/jgc4.1378DOI Listing
February 2021

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

Am J Hum Genet 2021 01;108(1):8-15

Molecular Medicine & Pathology and Pediatrics, McMaster University, Hamilton, ON L8S 3K9, Canada.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820621PMC
January 2021

Correspondence on "The role of clinical response to treatment in determining pathogenicity of genomic variants" by Shen et al.

Genet Med 2021 03 6;23(3):586. Epub 2020 Nov 6.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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http://dx.doi.org/10.1038/s41436-020-01032-6DOI Listing
March 2021

Strategic vision for improving human health at The Forefront of Genomics.

Nature 2020 10 28;586(7831):683-692. Epub 2020 Oct 28.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward-that is, at 'The Forefront of Genomics'.
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http://dx.doi.org/10.1038/s41586-020-2817-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869889PMC
October 2020

Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies.

Am J Hum Genet 2020 11 26;107(5):932-941. Epub 2020 Oct 26.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Boston, MA 02139, USA.

Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675005PMC
November 2020

Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice.

Hum Mol Genet 2020 12;29(20):3350-3360

Molecular Genomics and Metabolic Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA.

Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring that was heterozygous for both Cre and the conditional allele (βA-Akt1WT/flx) was viable. Fewer than expected numbers of βA-Akt1WT/flx embryos were seen beginning at E11.5, but a few survived until E17.5. The phenotype ranged from mild to severe, but generally βA-Akt1WT/flx embryos had fewer visible blood vessels and more hemorrhages than their wild-type littermates, which was suggestive of a vascular abnormality. Examination of E13.5 limb skin showed a primitive capillary network with increased branching complexity and abnormal patterning compared with wild-type skin. By E15.5, wild-type skin had undergone angiogenesis and formed a hierarchical network of remodeled vessels, whereas in βA-Akt1WT/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in βA-Akt1WT/flx skin compared with that of wild type. Restricting expression of Akt1E17K to endothelial, cardiac or smooth muscle cells resulted in viable offspring and remodeled vasculature and did not recapitulate the βA-Akt1WT/flx phenotype. We conclude that ubiquitous expression of Akt1E17K suppresses remodeling and inhibits the formation of a normal skin vasculature. We postulate that this failure prevents proper circulation necessary to support the growing embryo and that it is the result of interactions of multiple cell types with increased AKT signaling.
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http://dx.doi.org/10.1093/hmg/ddaa216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871364PMC
December 2020

Acne following Blaschko's lines in Proteus syndrome.

JAAD Case Rep 2020 Oct 20;6(10):1072-1074. Epub 2020 Aug 20.

Department of Dermatology, Uniformed Services University, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.jdcr.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509582PMC
October 2020

Prophylactic anticoagulation of individuals with Proteus syndrome and COVID-19.

Am J Med Genet A 2020 12 10;182(12):2829-2831. Epub 2020 Sep 10.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1002/ajmg.a.61861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942975PMC
December 2020

Genomic Screening for Malignant Hyperthermia Susceptibility.

Anesthesiology 2020 12;133(6):1277-1282

It is timely to consider the utility and practicability of screening for malignant hyperthermia susceptibility using genomic testing. Here the authors pose a simple, but bold question: what would it take to end deaths from malignant hyperthermia? The authors review recent advances and propose a scientific and clinical pathway toward this audacious goal to provoke discussion in the field.
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http://dx.doi.org/10.1097/ALN.0000000000003547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658016PMC
December 2020

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.

J Clin Endocrinol Metab 2021 03;106(3):e1441-e1452

National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina.

Context: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility.

Objective: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls.

Design: We compared patients with HA to control women.

Setting: The study was conducted at secondary referral centers.

Patients And Other Participants: Women with HA (n = 106) and control women (ClinSeq study; n = 468).

Interventions: We performed exome sequencing in all patients and controls.

Main Outcome Measure(s): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests.

Results: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%).

Conclusions: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.
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http://dx.doi.org/10.1210/clinem/dgaa609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947783PMC
March 2021

Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines.

Hum Mutat 2020 Oct 30;41(10):1734-1737. Epub 2020 Aug 30.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Recently, we demonstrated that the qualitative American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) guidelines for evaluation of Mendelian disease gene variants are fundamentally compatible with a quantitative Bayesian formulation. Here, we show that the underlying ACMG/AMP "strength of evidence categories" can be abstracted into a point system. These points are proportional to Log(odds), are additive, and produce a system that recapitulates the Bayesian formulation of the ACMG/AMP guidelines. The strengths of this system are its simplicity and that the connection between point values and odds of pathogenicity allows empirical calibration of the strength of evidence for individual data types. Weaknesses include that a narrow range of prior probabilities is locked in and that the Bayesian nature of the system is inapparent. We conclude that a points-based system has the practical attribute of user-friendliness and can be useful so long as the underlying Bayesian principles are acknowledged.
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http://dx.doi.org/10.1002/humu.24088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011844PMC
October 2020
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