Neonatally Lethal Fanconi Anemia due to an Amish Founder FANCE Gene Variant; Evidence for Genotype-Phenotype Correlation.

Prenatal and neonatal presentations of multiple congenital anomalies are difficult to diagnose and are associated with an increased risk of lethality. The differential diagnosis of antenatal presentations of radial ray malformations includes Fanconi anemia (FA), an inherited bone marrow failure disorder associated with congenital anomalies in around 75% of affected individuals. Although no definitive genotype-phenotype correlations have been demonstrated, a more severe presentation has been proposed in association with biallelic loss of function variants as opposed to hypomorphic missense variants. FA founder variants have been identified in several ethnic groups. Here we report the first description of a FANCE founder variant (FANCE NM_021922.3:c.1510-1G>A), in the Amish associated with multiple congenital anomalies and neonatal death in four individuals from an extended Amish pedigree comprising three nuclear families. Biparental whole exome sequencing was used to identify the candidate variant and confirmed in the homozygous state in affected individuals. All affected individuals had radial ray malformations, had at least one additional congenital anomaly, and died within the first day of life. We recommend that testing for this founder FANCE variant be considered in Amish individuals with a fetus or infant with multiple congenital anomalies, especially radial ray malformations.