This study sought to quantify uptake rates of non-invasive prenatal screening for de novo single-gene disorders (NIPS-SGD) in pregnant subjects whose reproductive partner is of advanced paternal age (APA) and to determine individual parameters associated with higher test uptake rates. A cross-sectional study was performed of pregnant subjects who received prenatal genetic counseling at a mid-size tertiary care center and were offered NIPS-SGD for APA (defined as 45 or older at delivery) between June 1, 2017 and April 13, 2021. We included non-anomalous, singleton gestations who conceived without donor egg/sperm. The outcome was measured as subjects who elected to do NIPS-SGD versus subjects who declined. Multivariable logistic regression was used to develop a model to discriminate between those who opted for testing and those who did not. 186 subjects were offered NIPS-SGD and met inclusion criteria. 70 had testing and 116 declined. Overall uptake rate was 38%. Several individual parameters were associated with higher test uptake including utilization of other screenings such as NIPS for aneuploidy (OR 3.4), carrier screening (OR 7.0) and invasive diagnostic testing (OR 8.4), presence of reproductive partner (OR 4.3), medicaid insurance (OR 2.6), and counseling at an offsite location (OR 2.0). AUC for the final regression model predicting NIPS-SGD uptake was 0.79. Based on this study, subjects who are information seekers and who opt for other prenatal screenings are more likely to pursue NIPS-SGD for de novo conditions associated with APA.

This cross-sectional survey study explores ongoing initiatives to foster diversity and inclusivity within the field of genetic counseling, specifically focusing on opportunities within graduate programs for students to enhance language and counseling skills in Spanish, thereby fostering language concordance in genetic counseling settings. With a response rate of 44.8% (26/58) across genetic counseling graduate programs, our study provides an overview of educational offerings in Spanish, encompassing patient-facing, non-patient-facing, and combined opportunities. Of the programs that completed the survey, 73.1% (19/26) offer Spanish language opportunities. Several perceived benefits were identified by those that offer opportunities, including fostering cultural humility and diversity within the field, increasing awareness and accessibility of genetic counseling services, and facilitating involvement in research within minority groups. The information gathered from this study can be a resource for graduate programs seeking insights into effective strategies to incorporate Spanish language opportunities. Additionally, these results may also serve as a source of inspiration for students who want to apply their Spanish language skills in their training and future careers. Lastly, we propose ideas to enhance and expand the training of bilingual genetic counseling students in Spanish.

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.

Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.

OBJECTIVE:To quantify carrier testing uptake rates for male partners of women found to be a carrier(s) for autosomal recessive conditions and to understand reasons for declining testing (uptake rate).METHODS:A retrospective chart review of 513 female patients seen at Rutgers-Robert Wood Johnson Medical School found to be carriers through expanded carrier screening (ECS) panels. The aims of this study were to determine how often their male partner chose testing, reasons for declining and the type of methodology chosen for their screening.RESULTS:Male partner uptake rate was 77%. We identified that the most significant barrier to male partner testing is female patients not following up on their own carrier screening results, thus missing the opportunity for partner testing. When male partners were provided options for testing, the most reported reason for declining is the belief it would have no impact on pregnancy management (20%). A carrier couple rate of 8.3% was identified of partners tested.CONCLUSION:Despite a relatively high male testing uptake rate, a quarter of carrier females did not proceed with testing their partner. To ascertain fetal risk, results for both parents is necessary. Pretest counseling should stress need for potential male partner follow-up testing.

............................................................................................... ii Acknowledgements................................................................................. ii