Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

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

Mayer-Rokitansky-Küster-Hauser syndrome patients' interest, expectations and demands concerning uterus transplantation

International audienceObjective - To better understand patients' conditions and expectations before starting a uterus transplantation (UTx) program for women suffering from Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome). Method - A web-based survey was conducted among MRKH patients via the French national association network from March to August 2020. The questionnaire comprised twenty-eight questions about their desire for parenthood, their condition's characteristics and previous reconstructive procedures, opinions and knowledge about UTx. Results - Among the 148 participants, 88 % reported a desire for parenthood, and 61 % opted for UTx as their first choice to reach this aim. The possibility of bearing a child and having the same genetic heritage were the main motivations. Once informed about the usual course of an UTx protocol, only 13 % of the participants changed their mind and 3 out of 4 of them opted for UT. Conclusion - Uterus transplantation seems to be the first option to reach motherhood in patients suffering from MRKH syndrome. The development of UTx programs could meet the demands of this already well-informed population

Recessive inheritance of DISP1 variants in holoprosencephaly spectrum patients

International audienc

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.

Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway

Mosaic intragenic deletion of FBN2

International audienc

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

<div><p>Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (<i>P</i> = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (<i>P</i> < 2.2 x 10⁻¹⁶), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, <i>GPR141</i>, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.</p></div

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

© 2016 Mitra et al.Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in f

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

© 2016 Mitra et al.Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in f

Linkage disequilibrium (LD) map of the region chromosome 7: 37.7Mb– 38.1 Mb.

<p>The graph displays LD between the SNPs rs114490548 (<i>P</i> = 7.8 x10^-11, Ras/MAPK ASD epistasis analysis) and rs62621010 (<i>P</i> = 5.6x10^-7, RASopathy QTL analysis). LD (D′) values for each pairwise comparison of SNPs were calculated based on LD and recombination rate data in 1000 Genomes May 2013 release and plotted using HAPLOVIEW(126) (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006516#sec027" target="_blank">web resources</a>) default settings and standard color theme. The red color corresponds to D’ = 1 and log of odds (LOD) ≥ 2, white corresponds to D’<1 and LOD <2, and blue to D’ = 1 and LOD<2.</p