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Am J Hum Genet ; 104(6): 1210-1222, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079897


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.

PLoS Genet ; 13(1): e1006516, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28076348


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.

Transtorno do Espectro Autista/genética , Epistasia Genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas ras/genética , Linhagem Celular , Feminino , Genes Modificadores , Estudo de Associação Genômica Ampla , Humanos , Masculino , Células-Tronco Neurais/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo
PLoS Genet ; 12(11): e1006425, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27846226


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 females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.

Transtorno do Espectro Autista/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Cromossomos Humanos X/genética , Transtorno do Espectro Autista/patologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Caracteres Sexuais
Eur J Med Genet ; 58(6-7): 341-5, 2015 Jun-Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25917374


Xp21 continuous gene deletion syndrome is characterized by complex glycerol kinase deficiency (GK), adrenal hypoplasia congenital (NROB1), intellectual disability and/or Duchenne muscular dystrophy (DMD). The clinical features depend on the size of the deletion, as well as on the number and the nature of the encompassed genes. More than 100 male patients have been reported so far, while only a few cases of symptomatic female carriers have been described. We report here detailed clinical features and X chromosome inactivation analysis in two unrelated female patients with overlapping Xp21 deletions presenting with intellectual disability and inconstant muscular symptoms.

Insuficiência Adrenal/genética , Erros Inatos do Metabolismo dos Carboidratos/genética , Cromossomos Humanos X/genética , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Glicerol Quinase/deficiência , Deficiência Intelectual/genética , Distrofia Muscular de Duchenne/genética , Insuficiência Adrenal/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Criança , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Glicerol Quinase/genética , Humanos , Hipoadrenocorticismo Familiar , Deficiência Intelectual/diagnóstico , Distrofia Muscular de Duchenne/diagnóstico , Síndrome , Adulto Jovem
Reprod Biomed Online ; 30(3): 290-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25599825


While chromosomal translocations are usually associated with a normal phenotype, they can still cause male infertility as well as recurrent miscarriages and fetal malformations related to their transmission in an unbalanced state. The distinction between balanced and unbalanced spermatozoa on morphological criteria is still unfeasible. However, we previously showed that: i) spermatozoa with an unbalanced content have a higher rate of DNA fragmentation; and ii) that density gradient centrifugation partially separates balanced from unbalanced sperm cells. We hypothesized that a chromosomal imbalance could alter the fine spermatic nuclear architecture and consequently the condensation of DNA, thus modifying normal sperm density. Spermatic nuclear volumes in four translocation carriers were analyzed using confocal microscopy. Secondarily, FISH analysis was used to establish the segregation mode of each spermatozoon. We found the average spermatic nuclei size to be higher among unbalanced spermatozoa in all patients but one. All the unbalanced modes were associated with larger nuclei in two patients, while this was the case for the 3:1 mode only in the other two, suggesting an abnormal condensation. This could be the first step in elaborating a procedure to completely eliminate unbalanced spermatozoa from semen prior to in vitro fertilization.

Transtornos Cromossômicos/patologia , Heterozigoto , Espermatozoides/patologia , Translocação Genética , Aborto Espontâneo/etiologia , Adulto , Desequilíbrio Alélico , Tamanho do Núcleo Celular , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/metabolismo , Transtornos Cromossômicos/fisiopatologia , Segregação de Cromossomos , Características da Família , Feminino , Corantes Fluorescentes/química , França , Humanos , Imagem Tridimensional , Hibridização in Situ Fluorescente , Infertilidade Masculina/etiologia , Substâncias Intercalantes/química , Masculino , Microscopia Confocal , Espermatozoides/metabolismo