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Two cases of 46, XY gonadal dysgenesis have been studied using molecular analysis. In one case, a 9p deletion was detected cytogenetically, while in the other case 9p appeared to be normal. In the first patient, the breakpoint was between D9S144 and D9S267, and the rearranged chromosome was of paternal origin. In the second case, the patient with the normal appearing 9p was hemizygous for markers D9S1858 and VLDLR, with a breakpoint possibly 6-8 cM from the telomere, a deletion that could not be observed through ordinary cytogenetic techniques because of the very terminal location.

More than a decade of massive DNA sequencing efforts have generated a large body of genomic, transcriptomic and epigenomic information that has provided a more and more detailed view of the functional elements and transactions within the human genome. Considerable efforts have also focused on linking these elements with one another by mapping their interactions and by establishing 3‐dimensional (3D) genomic landscapes in various cell and tissue types. In parallel, multiple studies have associated genomic deletions, duplications and other rearrangements with human pathologies. In this review, we explore recent progresses that have allowed connecting disease‐causing alterations with perturbations of the 3D genome organization. [ABSTRACT FROM AUTHOR]

Primary ovarian insufficiency ( POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c. 1483G>T [p. E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum. [ABSTRACT FROM AUTHOR]