TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature.

You-Hoover-Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene. Affected individuals were reported to have global developmental delay, intellectual disability, microcephaly, dysmorphic facial features, ocular involvement including cortical visual impairment, strabismus, cataract and rotatory nystagmus, movement disorder, hypertonia and spasticity, balance disturbance and ataxia, and abnormal sleep pattern. Other features reported include poor growth, cleft palate, cardiac malformations, epilepsy, scoliosis, and hearing loss. To date, 12 individuals with YHFS have been reported in the literature. Here we describe 14 new individuals with YHFS from 10 families. Their clinical presentation provides additional support of the phenotype recognized previously and delineates the clinical spectrum associated with YHFS syndrome. In addition, we present a review of the literature including follow-up data on four previously reported individuals with YHFS.

A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification.

Progressive corneal opacification can result from multiple etiologies, including corneal dystrophies or systemic and genetic diseases. We describe a novel syndrome featuring progressive epithelial and anterior stromal opacification in a brother and sister and their mildly affected father, with all three family members having sensorineural hearing loss and two also with tracheomalacia/laryngomalacia. All carried a 1.2 Mb deletion at chromosome 13q12.11, with no other noteworthy co-segregating variants identified on clinical exome or chromosomal microarray. RNAseq analysis from an affected corneal epithelial sample from the proband's brother revealed downregulation of XPO4, IFT88, ZDHHC20, LATS2, SAP18, and EEF1AKMT1 within the microdeletion interval, with no notable effect on the expression of nearby genes. Pathway analysis showed upregulation of collagen metabolism and extracellular matrix (ECM) formation/maintenance, with no significantly down-regulated pathways. Analysis of overlapping deletions/variants demonstrated that deleterious variants in XPO4 were found in patients with laryngomalacia and sensorineural hearing loss, with the latter phenotype also being a feature of variants in the partially overlapping DFNB1 locus, yet none of these had reported corneal phenotypes. Together, these data define a novel microdeletion-associated syndromic progressive corneal opacification and suggest that a combination of genes within the microdeletion may contribute to ECM dysregulation leading to pathogenesis.

Design and Outcomes of a Novel Multidisciplinary Ophthalmic Genetics Clinic.

The Multidisciplinary Ophthalmic Genetics Clinic (MOGC) at the University of Michigan Kellogg Eye Center aims to provide medical and ophthalmic genetics care to patients with inherited ocular conditions. We have developed a clinical and referral workflow where each patient undergoes coordinated evaluation by our multidisciplinary team followed by discussions on diagnosis, prognosis, and genetic testing. Testing approaches are specific to each patient and can be targeted (single-gene, gene panel), broad (chromosomal microarray, whole-exome sequencing), or a combination. We hypothesize that this clinic model improves patient outcomes and quality of care. A retrospective chart review of patients in the MOGC from July 2020 to October 2022 revealed that the most common referral diagnoses were congenital cataracts, optic neuropathy, and microphthalmia, with 52% syndromic cases. Within this patient cohort, we saw a 76% uptake for genetic testing, among which 33% received a diagnostic test result. Our results support a tailored approach to genetic testing for specific conditions. Through case examples, we highlight the power and impact of our clinic. By integrating ophthalmic care with medical genetics and counseling, the MOGC has not only helped solve individual patient diagnostic challenges but has aided the greater population in novel genetic discoveries and research towards targeted therapeutics.

Disclosure of clinically actionable genetic variants to thoracic aortic dissection biobank participants.

BACKGROUND: Disclosure of pathogenic variants to thoracic aortic dissection biobank participants was implemented. The impact and costs, including confirmatory genetic testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, were evaluated. METHODS: We exome sequenced 240 cases with thoracic aortic dissection and 258 controls, then examined 11 aortopathy genes. Pathogenic variants in 6 aortopathy genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 participants, representing 10.8% of the cohort (26/240). A second research sample was used to validate the initial findings. Mailed letters to participants disclosed that a potentially disease causing DNA alteration had been identified (neither the gene nor variant was disclosed). Participants were offered clinical genetic counseling and confirmatory genetic testing in a CLIA laboratory. RESULTS: Excluding 6 participants who were deceased or lost to follow-up, 20 participants received the disclosure letter, 10 of whom proceeded with genetic counseling, confirmatory genetic testing, and enrolled in a survey study. Participants reported satisfaction with the letter (4.2 ± 0.7) and genetic counseling (4.4 ± 0.4; [out of 5, respectively]). The psychosocial impact was characterized by low decisional regret (11.5 ± 11.6) and distress (16.0 ± 4.2, [out of 100, respectively]). The average cost for 26 participants was $400, including validation and sending letters. The average cost for those who received genetic counseling and CLIA laboratory confirmation was $605. CONCLUSIONS: Participants were satisfied with the return of clinically significant biobank genetic results and CLIA laboratory testing; however, the process required significant time and resources. These findings illustrate the trade-offs involved for researchers considering returning research genetic results.

When Genetics Meets Religion: What Scientists and Religious Leaders Can Learn from Each Other.

INTRODUCTION: To date scientists and religious leaders have not yet engaged in sustained face-to-face conversation concerning precision public health-related genetic technologies. OBJECTIVES: To elucidate areas of commonality and divergence in scientists' and religious leaders' views of precision genetic technologies, and extract lessons conveyed by religious leaders to scientists, and scientists to religious leaders through participatory dialogue. METHODS: Six 1.5-h dialogue sessions were held between 6 religious leaders, 8 University of Michigan scientists, and 3 additional public health/genetic counseling graduate students between October 2016 and September 2017, followed by an open conference at the Ann Arbor Public Library (n = 46). Statements were organized into thematically arranged duets comparing views of scientists and religious leaders. Duets were further ordered into interpretive levels. Comparative techniques were used to assure category agreement and face validity. RESULTS: The analysis yielded 20 duets and 3 interpretive levels (expositional; implications and consequences; and integrative, bridging concepts). Scientists emphasized the value of epigenetic testing for health promotion, and cost saving for some forms of early genetic testing for adult-onset conditions. Religious leaders stressed care for an individual's willingness to change over technical fixes for behavioral conditions and, together with public participants, the importance of allocating money for societal needs. Both expressed caution on the use of nuclear transfer for mitochondrial DNA replacement and secondary uses of genetic data. Lay conference participants pointed towards a middle ground on the release of genetically edited mosquitoes for disease eradication. DISCUSSION: Scientists stressed the value of professional guidance; religious leaders listened to family needs. Dialogues met four literature-based criteria for stakeholder involvement in deliberative processes. CONCLUSION: While scientists and religious leaders differ in their points of emphasis and faith orientations (professional competency versus drawing on compassion), they can successfully collaborate in reaching mutual understanding and specific areas of agreement on precision genetic technologies relating to public health.