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    Likely damaging variants associate with worse outcomes in congenital disorder

    For 1 in 3000 babies with congenital diaphragmatic hernia (CDH), the diaphragm does not close during development. The resulting defect allows abdominal organs to migrate into the chest and impairs lung development. Pulmonary hypertension (PH) often develops among CDH cases. In an effort to demonstrate how damaging genetic variants that cause congenital anomalies have pleiotropic effects that lead to worse outcomes, Qiao and colleagues show in this issue that a subset of likely damaging (LD) de novo genetic variants are associated with higher mortality, more prevalent PH, and poorer neurodevelopment in CDH patients. The researchers performed genomic sequencing on more than 460 CDH patients and their parents. They classified cases with only a diaphragm defect as isolated and those with one or more additional congenital anomalies as complex. They then assessed clinical outcomes between patients with or without LD variants. The researchers found that the mortality rate was higher in complex cases (31%) than in isolated cases (13%) and higher in LD cases than in non-LD cases. Isolated cases with LD variants had a mortality rate (31%) similar to that for complex cases. When the researchers assessed the prevalence of PH among cases, they found a similar trend. PH was significantly more common in LD cases than in non-LD cases at 1 month of age, with isolated LD cases showing a prevalence similar to that for complex cases. Finally, the researchers evaluated neurodevelopment among cases at 2 years of age. The analysis revealed that patients with LD variants showed worse motor and cognitive function, as well as worse adaptive behavioral skills, than non-LD patients. The authors conclude that LD genetic variants are associated with worse outcomes among CDH cases with implications for prognosis, interventions, and follow-up care for patients. —V. L. Dengler, News Editor

    Missense variant in DNA polymerase likely pathogenic in familial cancer

    Colorectal cancer is the third most common cancer in the United States, and familial cancers affect between 5% and 10% of cases. Germline missense variants in the proofreading domain of two DNA polymerases—POLE and POLD1—render carriers susceptible to several colorectal adenomas and carcinomas and lead to polymerase proofreading-associated polyposis syndrome (PPAP). Mur and colleagues determined the prevalence of POLE and POLD1 variants in hereditary cancer and evaluated the tumor spectrum of PPAP. The researchers sequenced POLE and POLD1 in a prospective cohort of more than 2300 unrelated hereditary cancer patients and a retrospective cohort of more than 500 unrelated cancer patients referred for genetic counseling. To aid variant interpretation, the team also performed cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses. The investigation identified 12 missense variants and 6 loss-of-function variants in the exonuclease domain (ED) of the polymerases and 23 missense variants outside the ED that are predicted to be deleterious. All of the identified variants have population allele frequencies of less than 1%. Using a number of variant interpretation analyses, including functional data, in silico predictors, and tumor mutation burden signatures, the researchers classified 4 of the 12 ED missense variants as likely benign, 7 as variants of unknown significance, and 1, POLE p.Met294 Arg, as likely pathogenic. The researchers determined that loss-of-function and POLE/POLD1 variants outside the ED are likely not pathogenic in PPAP. Colorectal, endometrial, and ovarian cancers were most commonly associated with PPAP. The authors conclude that PPAP comprises 0.1–0.4% of familial cancer cases. They also acknowledge that ED variant interpretation is complex and advise using multiple lines of evidence to overcome such challenges. —V. L. Dengler, News Editor

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    In This Issue. Genet Med (2020).

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