Expanded carrier screening (ECS) entails a screening offer for multiple recessive disorders at the same time, and allows testing of individuals or couples regardless of ancestry or geographic origin. Children of consanguineous couples have a higher-than-average risk of manifesting autosomal recessive disorders. This study aims to contribute to the responsible implementation of ECS for consanguineous couples. Seven semi-structured interviews were conducted with consanguineous couples who had recently participated in Whole Exome Sequencing (WES)-based ECS at Maastricht University Medical Center (MUMC+), the Netherlands. The test offered at MUMC+ covers a large number of disease-related genes (~2000), including severe, relatively mild, early- and late-onset disorders. Respondents were interviewed about their views on, and experiences with participation in WES-based ECS. Overall, participation was experienced as worthwhile: it enabled respondents to make informed choices with regard to family planning as well as to take on the presumed parental responsibility to deliver their children as healthy as possible. Furthermore, our findings suggest that (1) true consent for having this test requires timely information about the possible implications of a positive test result for specific categories of findings, as well as about the success rates of the available reproductive options; (2) the clinical geneticist can play a pivotal part in informing participants as well as providing clear information about autosomal recessive inheritance; (3) more research is needed to explore what type of genetic risk information is considered 'meaningful' by participants and actually contributes to reproductive decision-making.

RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.

PIK3CA pathogenic variants are responsible for a group of overgrowth syndromes, collectively known as PIK3CA-Related Overgrowth Spectrum (PROS). These gain-of-function variants arise postzygotically, and, according to time of onset, kind of embryonal tissue affected and regional body extension, give rise to heterogeneous phenotypes. PROS rarity and heterogeneity hamper the correct estimation of its epidemiology. Our work represents the first attempt to define the prevalence of PROS according to the established diagnostic criteria and molecular analysis and based on solid demographic data. We assessed the prevalence in Piedmont Region (Italy), including in the study all participants diagnosed with PROS born there from 1998 to 2021. The search identified 37 cases of PROS born across the 25-year period, providing a prevalence of 1:22,313 live births. Molecular analysis was positive in 81.0% of participants. Taking into account the cases with a detected variant in PIK3CA (n = 30), prevalence of molecularly positive PROS was 1:27,519.

Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available.

The coming-into-force of the EU General Data Protection Regulation (GDPR) is a watershed moment in the legal recognition of enforceable rights to informational self-determination. The rapid evolution of legal requirements applicable to data use, however, has the potential to outstrip the capabilities of networks of biomedical data users to respond to the shifting norms. It can also delegitimate established institutional bodies that are responsible for assessing and authorising the downstream use of data, including research ethics committees and institutional data custodians. These burdens are especially pronounced for clinical and research networks that are of transnational scale, because the legal compliance burden for outbound international data transfers from the EEA is especially high. Legislatures, courts, and regulators in the EU should therefore implement the following three legal changes. First, the responsibilities of particular actors in a data sharing network should be delimited through the contractual allocation of responsibilities between collaborators. Second, the use of data through secure data processing environments should not trigger the international transfer provisions of the GDPR. Third, the use of federated data analysis methodologies that do not provide analysis nodes or downstream users access to identifiable personal data as part of the outputs of those analyses should not be considered circumstances of joint controllership, nor lead to the users of non-identifiable data to be considered controllers or processors. These small clarifications of, or modifications to, the GDPR would facilitate the exchange of biomedical data amongst clinicians and researchers.

There have been reports of examples of exclusive yin yang haplotypes, differing at every locus, but there has been no systematic search for them. Unphased whole genome sequence data for 2504 unrelated 1000 Genomes subjects was searched for chains of SNPs having global minor allele frequency (MAF) > =0.1 made up of at least 20 SNPs in complete linkage disequilibrium with each other and with no pair being separated by more than 9 other SNPs. The global distribution of these haplotypes was investigated, along with their ancestral origins and associations with genes and phenotypes. A number of previously unrecognised repeats were noted, flagged by all or most subjects being called as heterozygotes, and these were discarded. There were 5114 exclusive yin yang haplotypes each consisting of on average 34.8 SNPs, each spanning on average 15.7 kb and cumulatively covering 80 Mb. Although for some haplotypes the MAF varied markedly between populations the average global fixation index was similar to that for SNPs elsewhere in the genome and there was no evidence of enrichment for genes or gene ontologies. For all but 92 haplotypes there were partial forms present in the chimpanzee and/or Neanderthal genome, indicating that they had been formed in a gradual process but that intermediate haplotypes were now absent from modern humans. Exclusive yin yang haplotypes cover over 2% of the human genome. The mechanisms accounting for their formation and preservation are unclear. They may serve as useful markers of the dispersal of chromosomal regions through human history.

Erratum in Eur J Hum Genet. 2023 Jun 19;: