De Novo Variants Associated With Autosomal Recessive Conditions: Case Series and Implications for Genetic Testing and Counseling.

The vast majority of individuals with autosomal recessive (AR) conditions demonstrate biparental inheritance of the disease-causing alleles; however, de novo variants also contribute to AR disease. This report represents the largest cohort to-date of rare AR conditions in which one of the disease-causing alleles was inherited and one occurred de novo. Clinical and research staff at Stanford University, clinical sites of the Undiagnosed Diseases Network (UDN) and Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, and a large clinical genetic testing laboratory were contacted to identify cases of an AR diagnosis resulting from an inherited and de novo disease-causing variant in trans. Fifteen cases of AR conditions caused by one inherited and one de novo variant in a gene consistent with the clinical phenotype were identified; all had undergone trio exome or genome sequencing with genetic confirmation of reported relationships. Variants were confirmed to be in trans in eight of the 15 cases. The de novo variant was confirmed (n = 7) or presumed (n = 7) to have arisen on the paternal allele in 14/15 (93%) of cases. Phenotypic and/or molecular evidence of an AR condition should prompt parental segregation analysis to inform diagnosis, recurrence risks, and variant classification. Additional studies are needed to determine the incidence of this phenomenon given the implications for the interpretation of genetic testing and counseling for AR conditions.