We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities. KMT2E (GenBank: NM_182931.2, MIM: 608444) encodes a member of the lysine N-methyltransferase 2 (KMT2) family. This family of enzymes plays a vital role in regulating post-translational histone methylation of histone 3 on lysine 4 (H3K4). 1 Proper H3K4 methylation is required to maintain open chromatin states for regulation of transcription. There are at least eight known monogenic disorders that impair regulation of H3K4 methylation and that

No abstract

No abstract

Objectives: Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders. Prenatal or preconception CF screening is offered in some countries. A maternal blood sample in early pregnancy can provide circulating trophoblasts and offers a DNA source for genetic analysis of both the mother and the fetus. This study aimed to develop a cell-based noninvasive prenatal test (NIPT) to screen for the 50 most common CF variants.Methods: Blood samples were collected from 30 pregnancies undergoing invasive diagnostics and circulating trophoblasts were harvested in 27. Cystic fibrosis testing was conducted using two different methods: by fragment length analysis and by our newly developed NGS-based CF analysis.Results: In all 27 cases, cell-based NIPT provided a result using both methods in agreement with the invasive test result. Conclusion:This study shows that cell-based NIPT for CF screening provides a reliable result without the need for partner-and proband samples. Key points What's already known about this topic?� Many pregnant women are positive towards prenatal screening for Cystic fibrosis (CF).� The only current pregnancy marker is echogenic bowel in the second trimester, but this test has low sensitivity and specificity. What does this study add?� Prenatal screening for CF can be done using circulating trophoblasts isolated from maternal blood early in pregnancy � Circulating trophoblasts can provide screening for CF as a simple single-visit setup without the need for a paternal sample.The data will be included in a presentation by author Line Dahl Jeppesen at CoGEN in start of November 2022.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements.

Objectives:The aim of the present study was to stratify the risk of detecting a pathogenic copy number variants (CNVs) by array comparative genomic hybridisation (aCGH) in relation to the first trimester Nuchal Translucency (NT) value. Methods: All women who underwent an invasive prenatal sampling for aCGH between 2008 and March 2017 were retrieved from the hospital database. Cases with genomic imbalances > 5MB were excluded because of their detectability by conventional karyotype. The first trimester NT values of the study population were reviewed and expressed in Multiple of Median (MoM) related to the Crown-rump length of the fetus. Maternal age, CRL measurement and NT values were compared between cases with and without aCGH anomaly. The incidence of aCGH anomalies in 5 sub-groups of NT value: ≥4; 3.0-3.9; 2.0-2.9; 1.0-1.9 and ≤1 MoM was evaluated. Additionally, Odds Ratio (OR) for a CGH anomaly was calculated for the foetuses with NT≥2 MoM compared to those <2MoM. Results: Over a 9-years period, a total of 2335 women received array CGH in our institution for different indications (structural ultrasound anomalies, positive screening for Trisomy 21, history of chromosomal anomaly). The overall incidence of pathogenetic CNVs was 4.9%. No differences were found in the distribution of maternal age and CRL measurement between women with or without aCGH anomaly, while NT values were statistically higher in the group with aCGH anomaly. The incidence of pathogenic CNVs among the different NT sub-groups was 9,0%, 7,5% 7,1% 4,7% 4,4% respectively (p=0.03). The OR for having a pathogenic CNVs in presence of NT values ≥2 MoM was 1.7 (95%CI 1,06-2,79; p=0.03) respect to NT values < 2 MoM. Conclusions:The results of the study suggest that the risk of aCGH anomalies increases exponentially with increasing the NT value. OC21.04Chromosomal microarray as a primary diagnostic genomic tool for pregnancies defined as being at increased risk within a population-based combined first trimester screening program Objectives: To evaluate the impact of using high-resolution chromosomal microarray (CMA) as the standard diagnostic approach to examine for genomic imbalances in pregnancies with increased risk (≥1 in 300) defined through combined first trimester screening (cFTS). Methods: A retrospective cohort of 575 consecutive pregnancies that had cFTS risk >1:300 through a publicly funded population based screening program in the Central and Northern Regions of Denmark between September 2015 and September 2016. Women with an NT ≥3.5mm, fetal malformation or opting for NIPT were excluded. Comparative genomic hybridisation was performed using a 180K oligonucleotide array on DNA extracted directly from samples. Genomic outcomes are reported in relation to cFTS findings. Results: 22 cases (22/575, 3.8%; 95% CI: 2.5-5.7%) of Trisomy 13, 18 and 21 were detected. A further 14 cases (14/575, 2.4%; 95% CI: 1.4-4.0%) of other types of aneuploidy were detected as well as 15 (15/575, 2.6%: 95% CI: 1.5-4.3%) cases with a pathogenic or likely pathogen...

No abstract

Objective: To examine the extent to which sex chromosomes are included in current noninvasive prenatal testing (NIPT) and the reporting practices with respect to fetal chromosomal sex and sex chromosome aberrations (SCAs), in addition to an update on the general implementation of NIPT.Method: A questionnaire addressing the research objectives was distributed by email to fetal medicine and clinical genetics experts in Asia, Australia, Europe and the USA.Results: Guidelines on NIPT are available in the majority of the included countries. Not all existing guidelines address reporting of fetal chromosomal sex and SCAs. In most settings, NIPT frequently includes sex chromosomes (five Australian states,