Parents' and adolescents' perspectives and understanding of information about childhood cancer precision medicine.

BACKGROUND: Precision medicine is projected to become integral to childhood cancer care. As such, it is essential to support families to understand what precision medicine entails. METHODS: A total of 182 parents and 23 adolescent patients participating in Precision Medicine for Children with Cancer (PRISM), an Australian precision medicine clinical trial for high-risk childhood cancer, completed questionnaires after study enrollment (time 0 [T0]). Of the parents, 108 completed a questionnaire and 45 completed an interview following return of precision medicine results (time 1 [T1]). We analyzed the mixed-methods data comprising measures exploring families' perceptions and understanding of PRISM's participant information sheet and consent form (PISCF), and factors associated with understanding. RESULTS: Most parents were satisfied with the PISCF, rating it as at least "somewhat" clearly presented (n = 160/175; 91%) and informative (n = 158/175; 90%). Many suggested improvements including the use of clearer language and a more visually engaging format. Parents' actual understanding of precision medicine was low on average, but scores improved between T0 and T1 (55.8/100-60.0/100; p = .012). Parents from culturally and/or linguistically diverse backgrounds (n = 42/177; 25%) had lower actual understanding scores than those from a Western/European background whose first language was English (p = .010). There was little correlation between parents' perceived and actual understanding scores (p = .794; Pearson correlation -0.020; 95% CI, -0.169 to 0.116). Most adolescent patients read the PISCF either "briefly" or "not at all" (70%) and had a perceived understanding score of 63.6/100 on average. CONCLUSIONS: Our study revealed gaps in families' understanding of childhood cancer precision medicine. We highlighted areas for potential intervention such as through targeted information resources. PLAIN LANGUAGE SUMMARY: Precision medicine is projected to become part of the standard of care for children with cancer. Precision medicine aims to give the right treatment to the right patient and involves several complex techniques, many of which may be challenging to understand. Our study analyzed questionnaire and interview data from parents and adolescent patients enrolled in an Australian precision medicine trial. Findings revealed gaps in families' understanding of childhood cancer precision medicine. Drawing on parents' suggestions and the literature, we make brief recommendations about improving information provision to families, such as through targeted information resources.

NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice.

Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Parents' understanding of genome and exome sequencing for pediatric health conditions: a systematic review.

Genome and exome sequencing (GS/ES) are increasingly being used in pediatric contexts. We summarize evidence regarding the actual and perceived understanding of GS/ES of parents of a child offered testing for diagnosis and/or management of a symptomatic health condition. We searched four databases (2008-2021) and identified 1264 unique articles, of which 16 met inclusion criteria. We synthesized data from qualitative and quantitative studies and organized results using Ayuso et al. (2013)'s framework of key elements of information for informed consent to GS/ES. Many of the parents represented had prior experience with genetic testing and accessed a form of genetic counseling. Parents' understanding was varied across the domains evaluated. Parents demonstrated understanding of the various potential direct clinical benefits to their child undergoing GS/ES, including in relation to other genetic tests. We found parents had mixed understanding of the nature of potential secondary findings, and of issues related to data privacy, confidentiality, and usage of sequencing results beyond their child's clinical care. Genetic counseling consultations improved understanding. Our synthesis indicates that ES/GS can be challenging for families to understand and underscores the importance of equipping healthcare professionals to explore parents' understanding of ES/GS and the implications of testing for their child.