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
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.
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