1071: Parental somato-gonadal mosaicism is a source of recurrence risk for de novo disorders: A meta-analysis

Abstract

Mosaic genetic variations, mutations arising during cell divisions post fertilization, are not found uniformly throughout the body. When occurring in germ cell progenitors, these may pass to offspring in a non-mosaic state causing apparent de novo mutations. Gonadal mosaicism leads to recurrence risk in subsequent pregnancies and some parental health concerns associate with low-level mosaic pathogenic variants. We sought to determine the spectrum of parental somato-gonadal mosaic variants (PSGMVs) reported in the literature. A systematic literature search using Pubmed, Medline, Pubmed Central, and Scopus was performed to identify primary reports of germline transmission of PSGMVs. Manual review permitted tabulation of variant information. To date, we reviewed 243 articles reporting 303 distinct cases. PSGMVs has been reported in broad groups of disorders including connective tissue, cancer predisposition, metabolic, and neurologic disorders. Fathers (135/256; 53%) and mothers (121/256; 47%) have equivalently been reported as the parent of origin for PSGMVs. The percent mosaicism of PSGMVs spans from less than 1% to greater than 60% with 80 of 168 (43%) cases with PSGMVs identified in parents falling in the 10% to 30% range. PSGMVs were detected in parental blood in 263/285 (92%) cases, other somatic tissues (e.g. fibroblasts, hair roots, tumors) in 13/285 (4.5%), and solely in germ cells in 9/285 (3.1%). In 41/303 (13.5%) cases, transmitting parents had features attributable to the variant including intellectual differences, seizures, dysmorphisms, or cancer. In 24/303 (8%) cases, prenatal genetic testing was applied in subsequent pregnancies. While parents of a child with apparent de novo mutation should consider targeted testing prenatally in subsequent pregnancies, few cases have been reported. Clinical screening tests for PSGMVs could affect recurrence risk and genetic counseling. This is extremely valuable for couples considering future pregnancies when a prior child was affected by an apparent de novo mutation.