Maternal plasma sequencing: a powerful tool towards fetal whole genome recovery

Noninvasive prenatal diagnosis of chromosomal aneuploidies, although challenging, has been achieved through the implementation of novel methodologies such as methylated DNA immunoprecipitation and next generation sequencing technologies. Nevertheless, additional developments are required towards the interpretation of other fetal abnormalities of higher complexity, such as de novo mutations including microdeletion and microduplication syndromes as well as complex diseases. The application of next generation sequencing technologies towards fetal whole genome recovery has demonstrated great potential to achieve the above goal. In a research article published in Genome Medicine, Chen et al. presented a novel approach that allowed more robust and accurate characterization of parental alleles compared with previous studies. This was achieved through a revolutionary strategy based on the use of trios and unrelated individuals that simultaneously targets the interpretation of the fetal haplotype and phenotype in one step. It is hereby shown that the implementation of a more accurate experimental design in combination with proper analytical tools can provide robust noninvasive fetal whole genome recovery with the potential for further developments beyond the DNA level

Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype

<p>Abstract</p> <p>Background</p> <p>Carriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of <it>de novo </it>cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six <it>de novo </it>and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all <it>de novo </it>cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype.</p> <p>Results</p> <p>Chromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two <it>de novo </it>(2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a <it>de novo </it>t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a <it>de novo </it>t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution.</p> <p>Conclusion</p> <p>This study investigated both <it>de novo </it>and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on <it>de novo </it>cases. This study provides additional evidence that cryptic genomic imbalances are common in patients with abnormal phenotype and "apparently balanced" translocations not only in <it>de novo </it>but can also occur in familial cases. The use of microarrays with higher resolution such as oligo-arrays may reveal that the frequency of cryptic genomic imbalances among these patients is higher.</p

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De novo unbalanced translocations have a complex history/aetiology

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here

The role of the European Society of Human Genetics in delivering genomic education

The European Society of Human Genetics (ESHG) was founded in 1967 as a professional organisation for members working in genetics in clinical practice, research and education. The Society seeks the integration of scientific research and its implementation into clinical practice and the education of specialists and the public in all areas of medical and human genetics. The Society works to do this through many approaches, including educational sessions at the annual conference; training courses in general and specialist areas of genetics; an online resource of educational materials (EuroGEMS); and a mentorship scheme. The ESHG Education Committee is implementing new approaches to expand the reach of its educational activities and portfolio. With changes in technology, appreciation of the utility of genomics in healthcare and the public's and patients' increased awareness of the role of genomics, this review will summarise how the ESHG is adapting to deliver innovative educational activity.Molecular Technology and Informatics for Personalised Medicine and Healt

Current use of noninvasive prenatal testing in Europe, Australia and the USA : A graphical presentation

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A SRY-HMG box frame shift mutation inherited from a mosaic father with a mild form of testicular dysgenesis syndrome in Turner syndrome patient

Background: Sex determining factor (SRY) located on the short arm of the Y chromosome, plays an important role in initiating male sex determination, resulting in development of testicular tissue. Presence of the SRY gene in females results in XY sex reversal and increased risk of gonadal germ cell tumours if the karyotype also includes the so-called GonadoBlastoma on the Y chromosome (GBY) region. The majority of mutations within the SRY gene are de novo affecting only a single individual in the family. The mutations within the high-mobility group (HMG) region have the potential to affect its DNA binding activity.Case Presentation: We performed G- and R-banding cytogenetic analysis of the patient and her family members including her father. We also performed molecular genetic analysis of SRY gene. Cytogenetic analysis in the patient (Turner Syndrome) revealed the mosaic karyotype as 45, X/46, XY (79%/21% respectively) while her father (milder features with testicular dysgenesis syndrome) has a normal male karyotype (46, XY). Using molecular approach, we screened the patient and her father for mutations in the SRY gene. Both patient and her father showed the same deletion of cytosine within HMG box resulting in frame shift mutation (L94fsX180), the father in a mosaic pattern. Histological examination of the gonads from the patient revealed the presence of gonadoblastoma formation, while the father presented with oligoasthenozoospermia and a testicular seminoma. The frameshift mutation at this codon is novel, and may result in a mutated SRY protein.Conclusion: Our results suggest that lack of a second sex chromosome in majority cells of the patient may have triggered the short stature and primary infertility, and the mutated SRY protein may be associated with the development of gonadoblastoma. It is of importance to note that mosaic patients without a SRY mutation also have a risk for malignant germ cell tumors