Rust, Laura

ABSTRACT Background Chondrodysplasia punctata 1 (CDPX1) is an X‐linked recessive disorder of cartilage and bone development characterized by stippling on the cartilage and bone, flattened nasal bridge, and brachydactyly, or short fingers. CDPX1 has been associated with variants in the ARSL gene and is known to manifest prenatally, however, there has been no systematic literature review on this evidence. Aims Here, we reviewed the current literature on prenatal manifestations of CDPX1, and additionally introduce previously unpublished cases. Materials & Methods A systematic review of the literature was performed. Additionally, a GeneMatcher submission was created and a call for cases was presented at the Fetal Sequencing Consortium meetings to find previously unpublished cases. Results For the 22 fetuses reported here, we found that 55% had nasal hypoplasia, 41% had bony stippling or calcifications, 32% had polyhydramnios, 5% had oligohydramnios, 23% had shortened long bones, 23% had spinal canal stenosis, 18% had ventriculomegaly, 9% had brachydactyly/brachytelephalangy, 9% had clubbed feet, 9% had premature rupture of membranes, and 9% had intraventricular hemorrhage detected through sonography or radiography. We also found 17 unique variants in ARSL for these 22 fetuses. Discussion A previously unpublished association of ARSL variants with intrauterine fetal death or stillbirth has been noted in this study. It is also possible that intracranial hemorrhage is an underrecognized feature associated with CDPX1 variation. However, there have been challenges in applying ACMG criteria to ARSL, a gene without an associated Variant Curation Expert Panel. Conclusion This literature review and case series highlights which features of CDPX1 manifest prenatally, as well as introduces new phenotypes that have not been previously identified.

AbstractGenetic counselors are trained to provide personalized genetic information and support to clients and their families. When requests for counseling comes from the counselor's own family member, should that counselor still provide service? There is a paucity of literature regarding genetic counselors counseling their own family members and no specific recommendations regarding how to reply to requests for genetic information from relatives. The purpose of this mixed methods study was to report genetic counselors’ and genetic counseling students’ perspectives and experiences providing genetic counseling to relatives. In the present study, 423 genetic counselors and genetic counseling students completed a 70‐item web‐based survey that explored genetic counselors’ experiences counseling family members outside of a clinic setting. The majority (73%; n = 301/410) of respondents have been asked to provide genetic counseling. Over half (57%; n = 257/423) provided counseling, personalized genetic information or risk assessment to family members. Only a small fraction of respondents (11%; n = 45/420) responded that they received any formal training in their graduate education, or in any other capacity that addressed the issue of how genetic counselors should respond to genetic counseling requests made family members. Those who have were less likely to provide genetic counseling to a family member (p < 0.05). Respondents who provided genetic counseling to relatives were significantly more likely to think their colleagues would do the same. Those who never provided genetic counseling to relatives were more likely to think their colleagues would refer to an unrelated genetic counselor (p < 0.0001). We highlight how our results have clinical and professional implications and provide suggestions to generate discussion among genetic counselors on how they might respond to requests for counseling from family members.