Teaching perspectives on the communication of difficult news of genetic conditions to medical students.

Informing parents that their child has a diagnosis of Down syndrome (DS) is a common example of the delivery of unexpected or difficult news. Expectations and life planning will change, and if detected prenatally, discussions might include the option of pregnancy termination. Medical school curricula currently include training in breaking unexpected news; however, it is difficult to teach and assess. We use the perspectives of clinicians, educators, and a medical student who is the parent of a child with DS to frame a discussion on teaching, practicing, and assessing communication of difficult news in human genetics during medical school.

Emotional intelligence in undergraduate medical students: a scoping review.

PURPOSE: To perform a scoping review to determine what is known about emotional intelligence (EI) in undergraduate medical education (UME). Two main questions were asked: A. What medical student characteristics are associated with EI? Are there correlations with demographic or other factors? B. What research studies have been done on EI in UME? For example, is there evidence EI changes over time as a result of personal experiences? Should EI be used as an admission criterion? Can EI improve as a result of experiences or deliberate interventions? METHOD: The authors searched four databases (PubMed, PsycInfo, Education Resources Information Center, and Web of Science) for all papers published up to and including December 2020. Two reviewers independently screened articles to determine if they met inclusion criteria. All authors extracted and analyzed data. RESULTS: A set of 1520 papers on the topic of emotional intelligence was identified, with 119 papers meeting inclusion criteria. Most studies were done at international locations with only 17 done at US medical schools. Seventy-five were cohort or cross-sectional studies. Study populations were mixed among the studies, with year of medical study, inclusion of other healthcare students, and participation rates among the inter-study differences noted. CONCLUSIONS: Numerous gaps in the literature on EI exist with several points being clear: (1) there is disagreement on the definition of EI, (2) it is undetermined whether EI is a trait or an ability, and (3) there is marked variability among the instruments used to measure EI. It is also becoming apparent that using EI determination may be helpful as a component of the admission process, higher EI is likely related to improved clinical reasoning, and higher EI contributes to more effective stress management.

Literature review: Genetic conditions or anomalies in artworks.

This is a literature review of publications describing artworks that include depictions of individuals with suspected genetic conditions or congenital anomalies. Types of artwork described in the identified papers included drawings, paintings, sculptures, carvings, or pottery. The papers included in this review consisted of general reviews, reviews of depictions of specific conditions, reviews of individual artists who had portrayed subjects with genetic conditions or anomalies, and artwork that generated discussions on possible diagnoses. Papers describing a single work were not included in this review.

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.

Correction: Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Training the next generation of genomic medicine providers: trends in medical education and national assessment.

PURPOSE: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®). METHODS: A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline. RESULTS: The committee identified 13.4%, 10.4%, and 4.4% of Steps 1, 2 and 3 respectively, as having genetics content. The genetics content of the exams became less pertinent to the questions from Step 1 to 3, with decreasing genetics content by exam and increasing percentages of questions identified as having genetics content in the distractors only. CONCLUSION: The current distribution of genetics in USMLE licensing examinations reflects traditional curricular approaches with genetics as a basic science course in the early years of medical school and de-emphasizes clinical relevance of the field. These observations support the notion that further integration is required to move genetics into the clinical curriculum of medical schools and the clinical content of USMLE Step exams.

Triallelic and epigenetic-like inheritance in human disorders of telomerase.

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.

Randomized trial finds that prostate cancer genetic risk score feedback targets prostate-specific antigen screening among at-risk men.

BACKGROUND: Prostate-specific antigen (PSA) screening may reduce death due to prostate cancer but leads to the overdiagnosis of many cases of indolent cancer. Targeted use of PSA screening may reduce overdiagnosis. Multimarker genomic testing shows promise for risk assessment and could be used to target PSA screening. METHODS: To test whether counseling based on the family history (FH) and counseling based on a genetic risk score (GRS) plus FH would differentially affect subsequent PSA screening at 3 months (primary outcome), a randomized trial of FH versus GRS plus FH was conducted with 700 whites aged 40 to 49 years without prior PSA screening. Secondary outcomes included anxiety, recall, physician discussion at 3 months, and PSA screening at 3 years. Pictographs versus numeric presentations of genetic risk were also evaluated. RESULTS: At 3 months, no significant differences were observed in the rates of PSA screening between the FH arm (2.1%) and the GRS-FH arm (4.5% with GRS-FH vs. 2.1% with FH: χ2 = 3.13, P = .077); however, PSA screening rates at 3 months significantly increased with given risk in the GRS-FH arm (P = .013). Similar results were observed for discussions with physicians at 3 months and PSA screening at 3 years. Average anxiety levels decreased after the individual cancer risk was provided (P = .0007), with no differences between groups. Visual presentation by pictographs did not significantly alter comprehension or anxiety. CONCLUSIONS: This is likely the first randomized trial of multimarker genomic testing to report genomic targeting of cancer screening. This study found little evidence of concern about excess anxiety or overuse/underuse of PSA screening when multimarker genetic risks were provided to patients. Cancer 2016;122:3564-3575. © 2016 American Cancer Society.

Update on the Toriello-Carey syndrome.

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. © 2016 Wiley Periodicals, Inc.

Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A.

Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, is a rare condition with fewer than 40 patients reported in the literature. Characteristic physical findings include neonatal progeroid appearance, sparse scalp hair, prominent scalp veins, and lipoatrophy; in addition, neonatal teeth are often a distinctive finding. The inheritance pattern of this disorder has been postulated to be autosomal recessive, although a specific gene has not been identified. Here we report an infant with the characteristic phenotypic features of Wiedemann-Rautenstrauch syndrome in whom exome sequencing identified two pathogenic variants in POLR3A: c.1909+18G>A; p.(Y637Cfs*23) and c.2617C>T; p.(R873*). Mutations in POLR3A (OMIM #614258) are associated with 4H leukodystrophy syndrome characterized by the triad of hypomyelination, hypodontia, and hypogonadotrophic hypogonadism. The present patient's genotype implies a broader phenotypic range for POLR3A mutations and might expand the clinical spectrum. This proband is notable because she had two null pathogenic variants. Replication in other patients clinically diagnosed with Wiedemann-Rautenstrauch syndrome is needed to further demonstrate this gene-disease association. © 2016 Wiley Periodicals, Inc.

2013 Review and Update of the Genetic Counseling Practice Based Competencies by a Task Force of the Accreditation Council for Genetic Counseling.

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non-clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors' roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre-defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force's work, key changes and the 2013 PBCs are presented herein.

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes.

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.

Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations.

Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS-targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria.

Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature.

The microcephaly-lymphedema-chorioretinal dysplasia (MLCRD) syndrome is a distinct microcephaly syndrome. The hallmark features, microcephaly, chorioretinopathy, and lymphedema are frequently recognized at birth. Another clinical entity, the chorioretinal dysplasia, microcephaly and mental retardation syndrome (CDMMR) is a highly overlapping syndrome characterized by more variable lymphedema. Recently, heterozygous mutations in KIF11, a gene encoding a critical spindle motor protein of the Kinesin family, have been reported in individuals with MLCRD, and in individuals with CDMMR. This finding is suggestive of a single clinically variable spectrum. Here, we report on de novo novel mutations of KIF11 in five individuals with severe microcephaly, marked simplification of the gyral pattern on neuroimaging, bilateral chorioretinopathy, and developmental delay. Three patients had congenital lymphedema, and one had congenital bilateral sensorineural hearing loss. This report, therefore, further expands the clinical and molecular spectrum of KIF11-associated microcephaly.

Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.

Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing.

MTHFR polymorphism testing is frequently ordered by physicians as part of the clinical evaluation for thrombophilia. It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous t-hromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as a part of a routine evaluation for thrombophilia.