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.

Movement of Genetic Counselors from Clinical to Non-clinical Positions: Identifying Driving Forces.

A previous study of genetic counselors (GCs) in the state of Indiana identified movement out of clinical positions within the past 2 years. The aims of this study were to determine if this trend is nationwide and identify reasons why GCs are leaving their positions and factors that might help employers attract and retain GCs. An email was sent to members of the American Board of Genetic Counseling with a link to an online confidential survey. There were 939 responses (23.5% response rate). Overall, 52% of GCs report being highly satisfied in their current position, although almost two thirds think about leaving and one third had changed jobs within the past 2 years. Of those who had changed jobs (n = 295), 74.9% had been working in a hospital/clinic setting but only 46.3% currently do, demonstrating a major shift out of the clinic (p < 0.001). The top three reasons cited for leaving a position were work environment/institutional climate, salary/benefits, and a lack of feeling valued/recognized as a professional. These results confirm that GCs are moving out of clinical positions and document elements of job satisfaction. We suggest points for employers to consider when trying to recruit or retain GCs.

Genetic Counselor Workforce Issues: a Survey of Genetic Counselors Licensed in the State of Indiana.

The aims of this study were to document movement of genetic counselors (GCs) out of clinical positions and identify factors that might help employers attract and retain clinical GCs. A confidential on-line survey of GCs ever licensed in the state of Indiana was conducted. Of the 46 respondents, most provide direct patient care (69.6 %), have worked in their current position for 5 years or less (72.1 %), and are experienced genetic counselors, having graduated between 6 and 15 years ago (43.5 %). One-third (32.6 %) reported thinking about leaving their current position at least monthly. GCs were more likely to think about leaving their current position when they provided direct patient care (p = 0.04) and worked in a hospital/clinic setting (p = 0.01). Among the 18 respondents that changed jobs in the past two years, 55.6 % currently work in a laboratory/industry setting and 44.4 % provide direct patient care, compared to 8 % of those in a stable position (N = 25) who work in a laboratory/industry setting (p < 0.01) and 88 % who provide direct patient care (p < 0.01). Genetic counselors who have changed jobs within the past 2 years were more satisfied with the possibility for advancement (p = 0.01), the recognition for work they do (p = 0.03) and feeling value from the organization (p = 0.04) in their current positions than those who have not changed jobs. Salary and flexibility were most often reported as reasons for changing jobs. This is the first documentation of the movement of GCs out of clinical roles into industry positions. This changing landscape may impact the access to clinical services and the training of genetic counseling students. This data will provide employers with data to help attract and retain GCs in clinical roles.

Heme and sensory neuropathy: insights from novel mutations in the heme exporter feline leukemia virus subgroup C receptor 1.

Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system mainly characterized by impaired nociception and autonomic dysfunction. We previously identified heme metabolism as a novel pathway contributing to sensory neurons maintenance and nociception. Indeed, we reported mutations in the feline leukemia virus subgroup C receptor 1 (FLVCR1) gene in individuals affected by HSAN. FLVCR1 gene encodes for 2 heme export proteins, FLVCR1a (plasma membrane) and FLVCR1b (mitochondria), crucially involved in the regulation of cellular heme homeostasis. Here, we report on 2 additional patients carrying novel biallelic mutations in FLVCR1 translation initiation codon (c.2T>C; p.(Met1Thr) and c.3G>T; p.(Met1Ile)). We overexpressed the c.2T>C; p.(Met1Thr) mutant in human cell lines and we describe its impact on protein structure and function in comparison with other HSAN-related mutations. We found that the mutation interferes with translation in 2 different ways: by lowering levels of translation of wild-type protein and by inducing translation initiation from a downstream in-frame ATG, leading to the production of an N-terminal truncated protein that is retained in the endoplasmic reticulum. The impact of different kinds of mutations on FLVCR1a localization and structure was also described. The identification of novel FLVCR1 mutations in HSAN reinforces the crucial role of heme in sensory neuron maintenance and pain perception. Moreover, our in vitro findings demonstrate that heme export is not completely lost in HSAN patients, thus suggesting the possibility to improve FLVCR1 expression/activity for therapeutic purposes.

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

Phenotypic spectrum of mosaic trisomy 18: two new patients, a literature review, and counseling issues.

Mosaic trisomy 18 occurs when two different cell lines exist in the same individual; one cell line has two copies of chromosome 18, while the other has three copies. Here we present two new patients with mosaic trisomy 18, summarize 31 reported cases from the literature, and discuss management and counseling themes. Our first patient is an 8(1/2)-year-old female with normal intelligence and no significant dysmorphic features other than short stature and cubitus valgus. The second patient is a 21-month-old male with developmental delay, several dysmorphic features, including a patent ductus arteriosus, and normal growth. In general, the phenotype of individuals with mosaic trisomy 18 varies greatly. Some individuals have the complete trisomy 18, Edwards syndrome phenotype with early death while others are phenotypically completely normal. The latter group is exemplified by four normal appearing adults with mosaic trisomy 18 who were identified only after giving birth to children with complete trisomy 18. Further, a wide range of anomalies have been reported, most at low frequencies, including microcephaly, delayed bone age, brachydactyly, congenital heart defects, developmental delay, short stature, and premature ovarian failure. Intellectual capabilities range from profound mental retardation to above average intelligence. There appears to be no correlation with the percentage of trisomic cells in either fibroblasts or leukocytes and the individual's phenotype or intellectual function. We also discuss a variety of counseling issues including long-term survival, reproductive capacity of individuals with mosaic trisomy 18, and recurrence risks.