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Genomic Autopsies Offer Diagnoses in Study of Perinatal Death Cases

COLD SPRING HARBOR, NY (GenomeWeb) – Genomic autopsies have been able to offer definitive genetic diagnoses in a handful of cases of perinatal death, according to the University of South Australia's Alicia Byrne.

In Australia, there are some 2,500 perinatal deaths each year, and Byrne noted that while current approaches can point to a congenital abnormality in some cases of perinatal death, they cannot say what caused that abnormality to occur.

As she reported during the Biology of Genomes meeting here, Byrne and her colleagues have used whole-exome and whole-genome sequencing to investigate perinatal death in more than a dozen families. In about half those cases, they were able to give genetic diagnoses, and for one family, this has informed their family planning choices.

"It is certain in the future, genomic autopsies will become the gold standard for investigations into perinatal death," Byrne said.

She added that such genomic autopsies also add to researchers' knowledge of what genes are critical for early human development.

Byrne and her colleagues have enrolled some 35 families in their study, 14 of which have already undergone sequencing. Nine families underwent whole-exome sequencing on the llumina HiSeq 250 platform and four underwent whole-genome sequencing on the Illumina X Ten.

For six families in the study, the researchers were able to determine the cause of perinatal death. In two cases, they homed in on known disease genes, and in two others they uncovered novel disease genes. In a further two cases, they also uncovered known disease genes, but ones that hadn't before been linked to fetal death. For another three families, Byrne said they uncovered candidate causative genes.

In one family, a consanguineous Indian couple, the researchers found a known disease gene behind their perinatal death that was associated with polycystic kidney disease.

For this family, Byrne and her colleagues filtered through four million variants to find a TMEM212 variant that co-segregated with disease. The variant was homozygous in affected and heterozygous in unaffected family members. TMEM, she noted, is expressed in human fetal kidneys, and knockout mice missing this gene had enlarged cystic kidneys and livers.

Byrne added that the couple used those findings to guide pre-implantation genetic diagnosis and now have a healthy baby boy.

At the same time, for a non-consanguineous Caucasian couple with two perinatal deaths associated with pseudodiastrophic dysplasia, the researchers homed in on a compound heterozygous mutation affecting B3GAT3. While B3GAT3 is a known disease gene, Byrne noted it has never been linked to a lethal fetal disorder, though the phenotype seen in the affected infants was similar to what's seen in other affected individuals.

Sanger sequencing confirmed the mutation in the affected family members, and Byrne added that both mutations appear to be loss-of-function mutations that lead to a severe decrease in enzymatic activity.

Byrne added that such genomic autopsies not only provide families with diagnoses, but also help identify important developmental genes as well as expand phenotypes associated with known genes.