Non-Invasive Prenatal Diagnosis (NIPD) has been one of the most fascinating research fields during the last decade. The identification of small amounts of fetal DNA in maternal circulation has opened new possibilities for NIPD. Up until today, two methods have achieved accurate and validated NIPD methods for trisomy 21. The first NIPD for trisomy 21 was based on next generation sequencing and the second was developed by our group and is based on a MeDIP real time qPCR. However, nothing has been achieved for the NIPD of other genomic disorders caused by pathogenic copy number changes or mutations. The primary goal of this proposal is to develop, validate and provide to clinical practice a novel NIPD method, which will enable fast, sensitive, accurate, robust and cost effective NIPD of the great majority of genetic disorders caused by either pathogenic copy number changes of genomic segments or single and small size mutations. Initially, biomarkers with differential methylation between fetal and maternal DNA located within the entire human exome will be identified using methylation DNA immunoprecipitation and whole-exome massive parallel sequencing. Then a novel MeDIP exome NGS NIPD method for the great majority (~85%) of genetic disorders will be developed and validated. The method will undergo a blind evaluation study using 300 normal and abnormal maternal peripheral blood samples of pregnant women at 10-12 week of gestation. The intellectual property which may arise will be protected by filing internationally PCT patent(s) followed by dissemination of the results of the project. The new method will not only provide a greater number of highly accurate prenatal diagnoses of genetic disorders, but will do so without any risk for the fetus. Thus, the provision of such prenatal diagnoses may be provided to all pregnant women. The proposed proposal goes beyond the current state of the art and provides multiple medical, social and economic benefits.