Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte.

Familial biparental hydatidiform mole (FBHM) is the only known pure maternal-effect recessive inherited disorder in humans. Affected women, although developmentally normal themselves, suffer repeated pregnancy loss because of the development of the conceptus into a complete hydatidiform mole in which extraembryonic trophoblastic tissue develops but the embryo itself suffers early demise. This developmental phenotype results from a genome-wide failure to correctly specify or maintain a maternal epigenotype at imprinted loci. Most cases of FBHM result from mutations of NLRP7, but genetic heterogeneity has been demonstrated. Here, we report biallelic mutations of C6orf221 in three families with FBHM. The previously described biological properties of their respective gene families suggest that NLRP7 and C6orf221 may interact as components of an oocyte complex that is directly or indirectly required for determination of epigenetic status on the oocyte genome.

The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.

We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.

Clinical phenotype associated with homozygosity for a HOXD13 7-residue polyalanine tract expansion.

Synpolydactyly (SPD) is an autosomal dominant malformation of the distal limbs caused by mutations in the homeobox gene HOXD13 located on chromosome 2q31. We detail the clinical findings in a consanguineous Pakistani family segregating a HOXD13 7-residue polyalanine tract expansion. Three members of this pedigree were heterozygotes with features typical of SPD. Two further members demonstrate a more severe phenotype consistent with homozygosity for the familial mutation. We also report a child from a consanguineous Somali family homozygous for the same molecular lesion. Characteristic changes include a complex central polydactyly in the hands, abnormal modelling of the metacarpals and metatarsals, an increased number of carpal bones with abnormal shapes, hypoplasia or absence of the fifth digital rays in the feet, hypoplasia of the middle phalanges and abnormally long proximal phalanges in hands and feet. These cases illustrate the distinct phenotype associated with homozygosity for a HOXD13 mutation and also highlight the importance of considering homozygosity for a dominant mutation in consanguineous pedigrees.