Publications by authors named "Andrea K Hanson-Kahn"

6 Publications

  • Page 1 of 1

Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.

HGG Adv 2021 Jan 14;2(1):100015. Epub 2021 Jan 14.

Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.

Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of , a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder.
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http://dx.doi.org/10.1016/j.xhgg.2020.100015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841527PMC
January 2021

Positive Attitudes and Therapeutic Misconception Around Hypothetical Clinical Trial Participation in the Huntington's Disease Community.

J Huntingtons Dis 2019 ;8(4):421-430

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Background: New therapies that could modify the disease course of Huntington's disease (HD) are entering clinical trials. However, conceptions about clinical research from the HD community are unknown. This knowledge could help inform patient-clinician discussions surrounding clinical trial participation.

Objective: The purpose of this study was to assess clinical trial attitudes and understanding in the HD community.

Methods: We developed a survey incorporating two measures of trial understanding and attitudes and the impact of therapeutic route of administration on hypothetical trial participation. The survey was distributed via emails, flyers, and social media through HD-related organizations.

Results: There were 73 responses. Individuals self-reported as clinically diagnosed with HD, gene positive but asymptomatic, or primary caregivers. Respondents viewed clinical trials positively and generally viewed trials as safe. Individuals with prior HD-related research experience were less likely to have negative expectations about trials than those without research experience (p = 0.002), and women had higher information needs than men (p = 0.001). Individuals with HD were more likely than the other groups to experience therapeutic misconception (p = 0.002). All respondents were able to appraise risks and benefits of research but exhibited optimism about trial outcomes. Willingness to participate was highest when the route of administration was minimally invasive.

Conclusions: While the HD community views clinical trials positively, patients with HD are at high risk for therapeutic misconception and all groups are optimistic about trial outcomes. Limitations of this study include a small sample that may be inclined to view research positively given past trial participation and interest in participating in HD surveys. However, the findings from this study can be used to strengthen informed consent during HD clinical trial recruitment.
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http://dx.doi.org/10.3233/JHD-190382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839474PMC
July 2020

Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students.

J Genet Couns 2019 04 1;28(2):466-476. Epub 2019 Feb 1.

Department of Genetics, Stanford University School of Medicine, Stanford, California.

With the wide adoption of next-generation sequencing (NGS)-based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture-based learning around these topics is important, there has been growing need for the inclusion of case-based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice.
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http://dx.doi.org/10.1002/jgc4.1094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456376PMC
April 2019

"This could be me": exploring the impact of genetic risk for Huntington's disease young caregivers.

J Community Genet 2019 Apr 14;10(2):291-302. Epub 2018 Nov 14.

Children's Hospital Oakland Research Institute, Oakland, CA, USA.

Huntington's disease (HD) is a predominantly adult-onset, genetic, neurodegenerative condition. Children of affected individuals have a 50% risk of inheriting HD and often assume caregiving roles for their parent. Studies specifically focused on HD young caregivers have proposed that the genetic risk component of HD "exacerbates" the caregiving experience and identified common responsibilities, burdens, and support needs, but none have explored the relationship between the caregiving role and perception of genetic risk. In an attempt to understand this relationship, we conducted a qualitative study to explore the interaction between a young caregiver's perception of genetic risk, the caregiving experience, and thoughts about and plans for predictive testing. Thirteen individuals between 15 and 25 years who provided care for a parent with HD were recruited from two HD youth groups and local support groups. Interviews were recorded, transcribed, and analyzed thematically. Two themes emerged: (1) caregiving and thoughts about risk and (2) caregiving and perceived opinions towards genetic testing. Our findings suggest that the genetic risk colors the caregiving experience by evoking feelings about the future and a potential diagnosis of HD, in addition to impacting plans for predictive testing. Genetic counselors can use these findings to inform their understanding of caregiver experiences, which can aid them when helping patients explore their motivations for testing during a genetic counseling session. Future studies should explore the extent to which health care providers acknowledge the work of young caregivers in the home and provide support to these individuals.
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http://dx.doi.org/10.1007/s12687-018-0395-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435781PMC
April 2019

-related intellectual disability syndrome: a recognisable entity.

J Med Genet 2017 09 22;54(9):613-623. Epub 2017 Jul 22.

Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Mutations in forkhead box protein P1 () cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.

Methods: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.

Results: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.

Conclusions: -related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.
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http://dx.doi.org/10.1136/jmedgenet-2017-104579DOI Listing
September 2017

Impact of Huntington Disease Gene-Positive Status on Pre-Symptomatic Young Adults and Recommendations for Genetic Counselors.

J Genet Couns 2016 12 22;25(6):1188-1197. Epub 2016 Apr 22.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder for which there is no cure. Predictive testing for HD is available to asymptomatic at-risk individuals. Approximately half of the population undergoing predictive testing for HD consists of young adults (≤35 years old). Finishing one's education, starting a career, engaging in romantic relationships and becoming a parent are key milestones of young adulthood. We conducted a qualitative study to explore how testing gene-positive for HD influences young adults' attainment of these milestones, and to identify major challenges that pre-symptomatic young adults face to aid the development of targeted genetic counseling. Results of our study demonstrate that 1) knowing one's gene-positive status results in an urgency to reach milestones and positively changes young adults' approach to life; 2) testing positive influences young adults' education and career choices, romantic relationships, and family planning; 3) young adults desire flexible and tailored genetic counseling to address needs and concerns unique to this population. Findings of this study contribute to the understanding of the impact of predictive testing for HD on young adults, and highlight issues unique to this population that call for further research, intervention and advocacy.
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http://dx.doi.org/10.1007/s10897-016-9951-zDOI Listing
December 2016