RESUMO
Although meiotic arrest in males is observed in about 25% of azoospermic patients, pure homogeneous arrest in all seminiferous tubules is less frequent, and may be due to mutation of a single gene. However, given the large number of genes involved in meiosis, this gives rises to extensive genetic heterogeneity. Only two genetic abnormalities have been reported on a regular basis: the X-linked exonic TEX11 deletion, and the AZFb microdeletion on the Y chromosome. Other single gene defects were private and found in consanguineous families. Here, we report on a homozygous missense mutation in the gene coding for meiotic double-stranded break formation protein 1 (MEI1; c.C3307T:p.R1103W) observed in two brothers (from a consanguineous Tunisian family) with non-obstructive azoospermia and meiotic arrest. A fertile brother was heterozygous for the mutation. All the queried databases predicted that this mutation is damaging, and it has previously been reported that Mei1 knock-out is associated with meiotic arrest in a murine model. Hence, meiotic arrest in the two brothers was probably caused by an alteration in a gene known to be fundamental for chromosome synapsis.
Assuntos
Azoospermia/congênito , Consanguinidade , Meiose/genética , Mutação de Sentido Incorreto/genética , Proteínas/genética , Azoospermia/genética , Proteínas de Ciclo Celular , Humanos , Masculino , Linhagem , Irmãos , Tunísia , Sequenciamento do ExomaRESUMO
Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. It was recently reported that a microdeletion at the 3q13.31 locus is associated with a new syndrome combining developmental delay, postnatal overgrowth and dysmorphic features. However, the reciprocal microduplication has only been described in a few case reports displaying some clinical features of the microdeletion syndrome. Here, we report on a female infant with a 3.34 Mb microduplication of the 3q13.2q13.31 region inherited from her mother. The infant presented with severe intellectual disability, learning difficulties, intrauterine and postnatal growth retardation and skeletal particularities but no dysmorphic traits. This microduplication encompassed the previously described shortest region of overlap, which contains five genes (DRD3, ZNF80, TIGIT, MIR568 and ZBTB20). We reviewed the phenotypes described in the literature on microduplications and in the well-characterized 3q13.31 microdeletion syndrome. In agreement with the literature data, DRD3 and ZBTB20 appear to be strong candidate genes for neurodevelopmental defects and growth retardation. Lastly, we consider the putative mechanism of this rearrangement, which may involve a particular kind of nonallelic homologous recombination of human endogenous retrovirus elements.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3 , Transtornos do Crescimento/genética , Criança , Cromossomos Humanos Par 3/genética , Feminino , Retardo do Crescimento Fetal/genética , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Proteínas do Tecido Nervoso/genética , Gravidez , Receptores de Dopamina D3/genética , Fatores de Transcrição/genéticaRESUMO
Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. Although homogeneous abnormalities can now be detected relatively easily using microarray technologies, they are more difficult to detect and interpret in cases of mosaicism. Here, we report on a male infant with a mosaic de novo derivative chromosome 9, featuring a 10.2 Mb 5q35 duplication (including the NSD1 gene) and a 687 kb 9q34 deletion (including EHMT1). The infant presented developmental delay, short stature, brachy/plagiocephaly and hyperactivity. The proportion of abnormal cells was 50% in saliva (in a microarray analysis) and 25% in lymphocytes (in a FISH analysis). Despite the low-level mosaicism in lymphocytes, this imbalance appears to be responsible for a distinctive phenotype (suggesting the presence of variable clinical expression and/or major somatic mosaicism).
Assuntos
Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Mosaicismo , Fenótipo , Pré-Escolar , Deleção Cromossômica , Anormalidades Craniofaciais/diagnóstico , Deleção de Genes , Duplicação Gênica , Cardiopatias Congênitas/diagnóstico , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Humanos , Deficiência Intelectual/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas Nucleares/genéticaRESUMO
KEY CLINICAL MESSAGE: Translocations between X and acrocentric chromosomes are rare. We report on the inheritance of a familial t(X;15)(p22.3;p10) translocation in a fetus referred for short long bones. Cytogenetic analysis revealed an unbalanced translocation combined with a three-gene nullosomy. After genetic counseling, a prognosis was established and a healthy boy was delivered.