Whole-genome sequencing reveals complex chromosome rearrangement disrupting NIPBL in infant with Cornelia de Lange syndrome.

Clinical laboratory diagnostic evaluation of the genomes of children with suspected genetic disorders, including chromosomal microarray and exome sequencing, cannot detect copy number neutral genomic rearrangements such as inversions, balanced translocations, and complex chromosomal rearrangements (CCRs). We describe an infant with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) in whom chromosome analysis revealed a de novo complex balanced translocation, 46,XY,t(5;7;6)(q11.2;q32;q13)dn. Subsequent molecular characterization by whole-genome sequencing (WGS) identified 23 breakpoints, delineating segments derived from four chromosomes (5;6;7;21) in ancestral or inverted orientation. One of the breakpoints disrupted a known CdLS gene, NIPBL. Further investigation revealed paternal origin of the CCR allele, clustering of the breakpoint junctions, and molecular repair signatures suggestive of a single catastrophic event. Notably, very short DNA segments (25 and 41 bp) were included in the reassembled chromosomes, lending additional support that the DNA repair machinery can detect and repair such segments. Interestingly, there was an independent paternally derived miniscule complex rearrangement, possibly predisposing to subsequent genomic instability. In conclusion, we report a CCR causing a monogenic Mendelian disorder, urging WGS analysis of similar unsolved cases with suspected Mendelian disorders. Breakpoint analysis allowed for identification of the underlying molecular diagnosis and implicated chromoanagenesis in CCR formation.

Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure.

Mutations in MCM9, which encodes DNA helicase, were recently shown to cause a clinical phenotype of primary ovarian failure and chromosomal instability. MCM9 plays an essential role in homologous recombination-mediated double-strand break repair. We describe a multiplex family with early colorectal carcinoma and mixed polyposis associated with primary hypergonadotropic hypogonadism. A combination of whole genome homozygosity mapping as well as exome sequencing and targeted gene sequencing identified a homozygous c.672_673delGGinsC mutation that predicts a truncated protein, p.Glu225Lysfs*4. Our data expand the phenotypic spectrum of MCM9 mutations and suggest a link between MCM9 and inherited predisposition to mixed polyposis and early-onset colorectal cancer.

"The Most Important Test You'll Ever Take"?: attitudes toward confidential carrier matching and open individual testing among modern-religious Jews in Israel.

This article reports on attitudes of modern-religious Ashkenazi Jewish adults in Israel toward anonymous carrier matching for severe monogenic diseases by Dor Yesharim (the ultra-orthodox organization) and open individual carrier testing (through a medical center), examining how this important choice is being informed, communicated, made, and reflected on. Qualitative analysis of semi-structured interviews conducted with 23 modern-religious Ashkenazi Jews in 2009-2011 revealed social pressure to utilize Dor Yesharim; however, respondents considered its policy of advising against a marriage between partners who are carriers of the same genetic condition inappropriate for 'love marriages' where a couple's commitment may already be made. Confidential carrier testing was a stepping stone to open carrier testing for those advised not to marry. Respondents varied in their views on when open carrier tests should be conducted. Pre-implantation genetic diagnosis was considered religiously preferable to abortion; however most carrier couples opted for pre-natal testing and selective abortion, challenging stereotypes about the attitudes of religious Jews. It is discussed how carrier screening is contextualized and interpreted not just in terms of religious teachings, but in interaction with lay agency, personal experiences and knowledge of reproductive choices. We conclude by discussing the implications for the social analysis of the ethics of carrier screening in religious communities at risk.