RESUMO
Premature ovarian insufficiency (POI) affects approximately 1% of women before the age of 40. Genetic contribution is a significant component of POI. In this context, heterozygous mutations in NOBOX, BMP15 and GDF9 have been reported. The objective of our study was to evaluate the prevalence of these genes mutations in 125 unrelated Tunisian patients diagnosed with POI. The screening of NOBOX gene revealed three missense mutations (p.Arg117Trp; p.Gly91Trp and p.Pro619Leu) in eight patients. These mutations were not found in a 200 ethnically matched women without fertility problem. The sequencing of BMP15 and GDF9 gene revealed only previously reported variants. In contrast to previous studies, the prevalence of BMP15 variations is not higher than in the control population. Conversely, 6.4% of the cases present a NOBOX mutations; this high prevalence strengthens the consideration of NOBOX gene as strong autosomal candidate for POI.
Assuntos
Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto , Insuficiência Ovariana Primária/genética , Fatores de Transcrição/genética , Adulto , Alelos , Análise Mutacional de DNA , Feminino , Frequência do Gene , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Genótipo , Humanos , Prevalência , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/epidemiologia , Tunísia/epidemiologiaRESUMO
We report on the cytogenetic and molecular characterization of a constitutional de novo ring chromosome 22 (r(22)) in 2 unrelated patients with emphasis on different hypotheses proposed to explain the phenotypic variability characterizing this genomic disorder. In both patients, molecular investigations using FISH and array-CGH techniques revealed a 22q terminal deletion involving the 22q13.33 critical region. The size of the deletion was estimated to at least 1.35 Mb in the first proband and to only 300 kb in the second. They both exhibited the major features of r(22) syndrome, but the first patient was more profoundly affected. He had a more severe phenotype, further complicated by behavioral anomalies, autistic-like features with abnormal EEG pattern and brain MRI profile. Haploinsufficiency of the SHANK3 gene, lying in the minimal critical region, is nowadays considered as responsible for most neurobehavioral anomalies. Nevertheless, phenotypic severity and occurrence of additional features in the first patient suggest a potential involvement of one or more specific gene(s) located proximally to SHANK3 (as PLXNB2, PANX2, ALG12 or MLC1), acting either independently of it or by regulating or promoting its expression and thus disrupting its function when deleted.