Accepting or declining preconception expanded carrier screening: An exploratory study with 407 couples.

Rapidly evolving genomic technologies have made genetic expanded carrier screening (ECS) possible for couples considering a pregnancy. The aim of ECS is to identify couples at risk of having a child affected with a severe disorder and to facilitate their reproductive decision-making process. The ECS test we offer at our center, called BeGECS (Belgian Genetic ECS), consists of 1268 autosomal recessive (AR) and X-linked pathogenic genes, including severe childhood-onset disorders. However, thus far data are scarce regarding the actual uptake of preconception ECS in a clinical setting. Therefore, our aim was to describe the characteristics of 407 couples to whom ECS was offered at the Center for Medical Genetics of the University Hospital Ghent (CMGG). In addition, we aimed to identify their reasons for accepting or declining BeGECS. Between October 2019 and January 2023, 407 preconception couples were offered BeGECS and were asked to fill in a questionnaire after their decision. Of the 407 couples participating in the survey, 270 (66%) decided to take the test and 137 (34%) declined. We observed that age, highest education level as well as indication for consultation were statistically different between the group that accepted to take the test and the group that declined (p = 0.037). In particular, age and education level were substantially higher in the group that accepted the test. Major reasons for taking BeGECS include prevention, wishing to obtain all information possible, helping preparing their future reproductive decision and increasing their sense of control by being informed. However, couples that do not chose to take BeGECS stated that too much information would make them anxious, that the result would not change their decision to have children, that they do not want to spend money on something that will not happen and that they do not worry about their family history. These findings show that the majority of preconception couples that were offered ECS, accepted the test.

CHD7 Disorder-Not CHARGE Syndrome-Presenting as Isolated Cochleovestibular Dysfunction.

CHARGE syndrome, characterized by a distinct set of clinical features, has been linked primarily to mutations in the CHD7 gene. Initially defined by specific clinical criteria, including coloboma, heart defects, choanal atresia, delayed growth, and ear anomalies, CHARGE syndrome's diagnostic spectrum has broadened since the identification of CHD7. Variants in this gene exhibit considerable phenotypic variability, leading to the adoption of the term "CHD7 disorder" to encompass a wider range of associated symptoms. Recent research has identified CHD7 variants in individuals with isolated features such as autism spectrum disorder or gonadotropin-releasing hormone deficiency. In this study, we present three cases from two different families exhibiting audiovestibular impairment as the primary manifestation of a CHD7 variant. We discuss the expanding phenotypic variability observed in CHD7-related disorders, highlighting the importance of considering CHD7 in nonsyndromic hearing loss cases, especially when accompanied by inner ear malformations on MRI. Additionally, we underscore the necessity of genetic counseling and comprehensive clinical evaluation for individuals with CHD7 variants to ensure appropriate management of associated health concerns.

A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.

Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.