POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

Loeys-Dietz syndrome caused by 1q41 deletion including TGFB2 is associated with a neurodevelopmental phenotype.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that commonly results in a dilated aorta, aneurysms, joint laxity, craniosynostosis, and soft skin that bruises easily. Neurodevelopmental abnormalities are uncommon in LDS. Two previous reports present a total of four patients with LDS due to pure 1q41 deletions involving TGFB2 (Gaspar et al., American Journal of Medical Genetics Part A, 2017, 173, 2289-2292; Lindsay et al., Nature Genetics, 2012, 44, 922-927). The current report describes an additional five patients with similar deletions. Seven of the nine patients present with some degree of hypotonia and gross motor delay, and three of the nine present with speech delay and/or intellectual disability (ID). The smallest deletion common to all patients is a 785 kb locus that contains two genes: RRP15 and TGFB2. Previous studies report that TGFB2 knockout mice exhibit severe perinatal anomalies (Sanford et al., Development, 1997, 124, 2659-2670) and TGFB2 is expressed in the embryonic mouse hindbrain floor (Chleilat et al., Frontiers in Cellular Neuroscience, 2019, 13). The deletion of TGFB2 may be associated with a neurodevelopmental phenotype with incomplete penetrance and variable expression.

Genetic counseling for congenital heart disease - Practice resource of the National Society of Genetic Counselors.

Congenital heart disease (CHD) is an indication which spans multiple specialties across various genetic counseling practices. This practice resource aims to provide guidance on key considerations when approaching counseling for this particular indication while recognizing the rapidly changing landscape of knowledge within this domain. This resource was developed with consensus from a diverse group of certified genetic counselors utilizing literature relevant for CHD genetic counseling practice and is aimed at supporting genetic counselors who encounter this indication in their practice both pre- and postnatally.

Genetics and Precision Medicine: Heritable Thoracic Aortic Disease.

Heritable thoracic aortic disease (HTAD) can have life-threatening consequences if not diagnosed early. Affected individuals and at-risk family members benefit from both cardiology and genetic evaluations, including genetic testing. Important information can be obtained through family history, medical history, and genetic testing to help guide management and assess risk. A genetic diagnosis can guide cardiovascular management (type and frequency of vascular imaging, timing of surgical intervention), risk assessment for arterial aneurysm/dissection, evaluation of nonvascular features, and familial testing.

Exploring the Discussion of Risk of Sudden Cardiac Death.

Sudden arrhythmic death syndrome (SADS), where death is secondary to cardiac arrhythmia, is associated with several cardiac ion channelopathies, including long QT syndrome and Brugada syndrome, as well as cardiomyopathies such as hypertrophic cardiomyopathy and dilated cardiomyopathy. Many of these conditions often present in childhood or adolescence. This study investigates how diagnoses of cardiac diseases associated with SADS are communicated within families. A questionnaire was distributed through cardiac disease-focused support groups and organizations. Data from 114 parents who have a child with a SADS condition were used for analysis. Based on the responses, parents explained the risk of SADS in a straightforward manner and related the risk to the importance of compliance with the prescribed treatment. Participants also found it difficult to determine and enforce lifestyle modifications, manage individuals' emotional reactions, convey the seriousness of the information without scaring their children, and discuss the risk of SADS during these conversations. Concerns regarding disease progression, length and quality of life, and treatment failures were also expressed. Healthcare providers, the Internet, other affected people, visual aids, and personal experience were all reported to be helpful for facilitating these discussions. Services and resources requested by participants included children's support groups, a counselor or psychologist, and child-oriented materials. Increased understanding of how families discuss children's diagnosis of SADS conditions will equip healthcare providers with the information to address parental concerns and help facilitate meaningful and informative discussions within families.

Genetic counseling and testing for hypertrophic cardiomyopathy: an adult perspective.

Hypertrophic cardiomyopathy (HCM) is considered to be a genetic disease. As such, multidisciplinary approach is needed to evaluate and treat this condition. We present several patient vignettes to illustrate the complementary skills of cardiologists and genetic counselors in providing comprehensive care. Translational application of research will continue to expand as more genetic causes of HCM will be recognized and more genetic tests will become available. Now is the opportunity to build a strong collaboration between the two disciplines to be prepared for the era of personalized medicine.

Genetic counseling and testing for hypertrophic cardiomyopathy: the pediatric perspective.

Hypertrophic cardiomyopathy (HCM) is a common cardiac disease that is now being identified in the pediatric population. The etiology of this disease is largely genetic, and as a result, genetics professionals are becoming more involved in the management of these patients. We present multiple case scenarios that highlight the complex nature of this disease and how genetic counselors and cardiologists can interact to identify the genetic etiology of HCM and provide comprehensive care for these patients. Additionally, we describe knowledge gaps in this field and how research endeavors can assist in more effectively managing this patient cohort.

Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?

BACKGROUND/AIMS: Glycogen storage disease III (GSD III) is caused by a deficiency of glycogen-debranching enzyme which causes an incomplete glycogenolysis resulting in glycogen accumulation with abnormal structure (short outer chains resembling limit dextrin) in liver and muscle. Hepatic involvement is considered mild, self-limiting and improves with age. With increased survival, a few cases of liver cirrhosis and hepatocellular carcinoma (HCC) have been reported. METHODS: A systematic review of 45 cases of GSD III at our center (20 months to 67 years of age) was reviewed for HCC, 2 patients were identified. A literature review of HCC in GSD III was performed and findings compared to our patients. CONCLUSIONS: GSD III patients are at risk for developing HCC. Cirrhosis was present in all cases and appears to be responsible for HCC transformation There are no reliable biomarkers to monitor for HCC in GSD III. Systematic evaluation of liver disease needs be continued in all patients, despite lack of symptoms. Development of guidelines to allow for systematic review and microarray studies are needed to better delineate the etiology of the hepatocellular carcinoma in patients with GSD III.