Familial biparental hydatidiform mole (FBHM) is a recessive disorder that results in repeated pregnancy loss due to a failure to establish maternal imprints at multiple loci throughout the genome. Previous work showed that some cases of FBHM result from biallelic mutations in NLRP7 (Nat. Genet. 38, 300–302, 2006). Eamonn Sheridan and colleagues (Am. J. Hum. Genet. 89, 451–458, 2011) now identify mutations in C6orf211 as a likely cause of FBHM in families not harboring NLRP7 mutations. Starting with a large consanguineous FBHM family for which linkage to NLRP7 had been excluded, the authors performed homozygosity mapping followed by targeted capture of all coding sequences from six regions of concordant homozygosity. Bioinformatic filtering for potentially damaging mutations highlighted a variant disrupting the initiation codon of C6orf221. Analysis of 14 further cases of recurrent hydatidiform mole identified two additional cases with biallelic inactivating mutations in C6orf221. Expression studies in human ovarian follicles, oocytes and preimplantation embryos showed peak C6orf221 transcript levels in germinal vesicle oocytes, similar to the expression profile previously reported for NLRP7, suggesting that the products of these two genes might act in a common pathway required for maternal imprinting.