Neuromuscular and cardiovascular phenotypes in paediatric titinopathies: a multisite retrospective study.

BACKGROUND: Pathogenic variants in TTN cause a spectrum of autosomal dominant and recessive cardiovascular, skeletal muscle and cardioskeletal disease with symptom onset across the lifespan. The aim of this study was to characterise the genotypes and phenotypes in a cohort of TTN+paediatric patients. METHODS: Retrospective chart review was performed at four academic medical centres. Patients with pathogenic or truncating variant(s) in TTN and paediatric-onset cardiovascular and/or neuromuscular disease were eligible. RESULTS: 31 patients from 29 families were included. Seventeen patients had skeletal muscle disease, often with proximal weakness and joint contractures, with average symptom onset of 2.2 years. Creatine kinase levels were normal or mildly elevated; electrodiagnostic studies (9/11) and muscle biopsies (11/11) were myopathic. Variants were most commonly identified in the A-band (14/32) or I-band (13/32). Most variants were predicted to be frameshift truncating, nonsense or splice-site (25/32). Seventeen patients had cardiovascular disease (14 isolated cardiovascular, three cardioskeletal) with average symptom onset of 12.9 years. Twelve had dilated cardiomyopathy (four undergoing heart transplant), two presented with ventricular fibrillation arrest, one had restrictive cardiomyopathy and two had other types of arrhythmias. Variants commonly localised to the A-band (8/15) or I-band (6/15) and were predominately frameshift truncating, nonsense or splice-site (14/15). CONCLUSION: Our cohort demonstrates the genotype-phenotype spectrum of paediatric-onset titinopathies identified in clinical practice and highlights the risk of life-threatening cardiovascular complications. We show the difficulties of obtaining a molecular diagnosis, particularly in neuromuscular patients, and bring awareness to the complexities of genetic counselling in this population.

U.S. Genetic counselors' perceptions of inpatient genetic counseling: A valuable model for medically complex patients.

Some genetic counselors (GCs) provide care in the inpatient setting. However, there is little literature on inpatient genetic counseling. The purpose of our study was to describe GC's experiences with the provision of genetic counseling services within inpatient care settings. Participants were recruited from respondents to a quantitative survey study on inpatient genetic counseling, which recruited GCs via the National Society of Genetic Counselors forum. GCs seeing at least five inpatients per year were invited to participate in semi-structured interviews. The interview guide explored how and why their inpatient genetic counseling service started, workflow, and the perceived impact of the service. Interviews were transcribed, inductive analysis was used to develop a codebook, and thematic analysis was used to identify themes. Twenty-one inpatient genetic counselors participated in the study. Many participants worked primarily in outpatient roles with some inpatient duties (61.9%), while the rest worked primarily in inpatient roles (38.1%). Most participants have provided inpatient care for <2 years (66.7%). Many participants were involved in inpatient care across multiple specialties (66.7%), most frequently, pediatrics, neonatology, and neurology. Three themes were identified: (a) The convenience of inpatient genetic counseling leads to increased access to appropriate genetics care for medically complex patients and their inpatient healthcare providers, (b) the inpatient genetic counseling process and workflow is not standard and has multiple moving parts, and (c) genetic counselors are fulfilled by the diverse and unique opportunities of the inpatient care setting despite the emotional intensity of this environment. Participants described their inpatient care as valuable because it increases access to genetics services and adds genetics expertise to multidisciplinary inpatient teams. Overall, participants perceive inpatient genetic counseling as a way to bring genetics care directly to patients at a critical time point in their care, which benefits medically complex patients and their multidisciplinary inpatient team.

Characterization of genetic counselor practices in inpatient care settings.

Rapid genomic testing is increasingly used in inpatient settings for diagnostic and treatment purposes. With the expansion of genetic testing in this setting, requests for inpatient genetics consultations have increased. There have been reports of genetic counselors working in inpatient care, though their specific roles are not well described. In this study, we characterized the roles of genetic counselors practicing in inpatient care settings in the United States and Canada. Genetic counselors were recruited via professional organization listservs to complete an online survey. The survey gathered information on participants' roles and workflow of inpatient genetics consultation services at their institution. Responses from 132 participants demonstrate that 50.4% of genetic counselors cover genetics consultations as needed or on a rotating schedule (34.6%). They practice in general pediatric (59.1%), neonatal (42.5%), cancer (28.3%), and/or prenatal (18.9%) specialties, among others. Participants reported working independently (16.1%) or with other providers (54.8%), including geneticists and other attending physicians. The workflow of genetics consultation services varies between institutions in the delivery of consults, members of the inpatient genetics consultation care team, and administrative support. Fifty percent of participants reported having no exposure to inpatients during graduate training, and 87.3% of participants reported receiving no institutional training for their inpatient role. This is the first study to describe roles of genetic counselors in inpatient care. It establishes a foundation for future research on inpatient genetic counseling and genetic counseling outcomes in inpatient services. As demand for genetics expertise in inpatient care grows, genetic counselors can be hired to serve inpatient populations alongside genetics and non-genetics providers.

Exploring the Medical and Psychosocial Concerns of Adolescents and Young Adults With Craniofacial Microsomia: A Qualitative Study.

OBJECTIVE: This study explores the experiences of adolescents and young adults with craniofacial microsomia, including the impact of growing up with this craniofacial condition on daily life and sense of self. The results may guide future research on optimally supporting individuals with craniofacial microsomia during this critical life phase. DESIGN AND SETTING: Participants were recruited through a craniofacial center, online patient support groups, and social media sites. Eleven individual semistructured interviews with participants between 12 and 22 years old were conducted by a single interviewer, transcribed, iteratively coded, and thematically analyzed. RESULTS: Five themes were evident in the data: (1) impact on personal growth and character development, (2) negative psychosocial impact, (3) deciding to hide or reveal the condition, (4) desire to make personal surgical decisions, and (5) struggles with hearing loss. CONCLUSIONS: We identified both medical and psychosocial concerns prevalent among adolescents with craniofacial microsomia. Although adolescents with craniofacial microsomia exhibit considerable resilience, the challenges they face impact their sense of self and should be addressed through psychosocial support and counseling. Further research should investigate the potential benefit of the wider use of hearing aids, as well as the involvement of patients in decision-making about reconstructive ear surgery.

Causative Variants for Inherited Cardiac Conditions in a Southeast Asian Population Cohort.

BACKGROUND: Variable penetrance and late-onset phenotypes are key challenges for classifying causal as well as incidental findings in inherited cardiac conditions. Allele frequencies of variants in ancestry-specific populations, along with clinical variant analysis and interpretation, are critical to determine their true significance. METHODS: Here, we carefully reviewed and classified variants in genes associated with inherited cardiac conditions based on a population whole-genome sequencing cohort of 4810 Singaporeans representing Southeast Asian ancestries. RESULTS: Eighty-nine (1.85%) individuals carried either pathogenic or likely pathogenic variants across 25 genes. Forty-six (51.7%) had variants in causal genes for familial hyperlipidemia, but there were also recurrent variants in SCN5A and MYBPC3, causal genes for inherited arrhythmia and cardiomyopathy, which, despite previous reports, we determined to lack criteria for pathogenicity. CONCLUSIONS: Our findings highlight the incidence of disease-related variants in inherited cardiac conditions and emphasize the value of large-scale sequencing in specific ancestries. Follow-up detailed phenotyping and analysis of pedigrees are crucial because assigning pathogenicity will significantly affect clinical management for individuals and their family members.

Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy.

BACKGROUND: Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A-band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. METHODS: Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype-phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. RESULTS: Forty-nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3') end of the A-band. All cardioskeletal probands had onset of proximal-predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. CONCLUSION: Although heterozygous TTNtv in the A-band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb-girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A-band TTNtv who may be at risk for multisystem disease.