Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.

Two sisters and their brother affected with microcephaly, microphthalmia, chorioretinal degeneration, and optic atrophy were studied. Besides the clinical features derived from the main abnormalities, nanosomy and cutis marmorata were found in the three patients. Both parents and three other sibs were normal. Possible intrauterine non-genetic etiologic factors (X-rays, toxoplasmosis, cytomegalovirus) which can lead to phenocopies were investigated with negative results. Based on these and previous observations, it seems clear that a distinct form of autosomal recessive microcephaly associated with chorioretinal degeneration can be separated from the heterogenous group of entities which presents microcephaly.

Three 46,XY unrelated individuals out of 84 postpubertal male inpatients with severe mental deficiency in a psychiatric hospital were found to have megalorchidia and macrogenitosomia. One of the cases had a similarly affected brother. Endocrine studies were performed in two of the cases with similar results. Normal plasma levels of pituitary gonadotropins were found. A normal testicular function was demonstrated by the finding of normal: (a) baseline plasma testosterone levels and a significant rise following human chorionic gonadotropin administration, (b) sperm analysis, and (c) morphology and cell architecture of the testes. These results were compatible with normofunctional testicular hyperplasia confirming previous observations and allowing the definite individualization of a syndrome with mental deficiency probably due to an X-linked recessive mutation.

An inv(1) (p3500q21.3) was found in an azoospermic man, his mother and two other maternal relatives. Although the mechanisms involved are still unclear, it is stressed that pericentric inversions of chromosome 1 in which the inverted chromosome becomes submetacentric (centromeric index less than or equal to 0.324) apparently impair spermatogenesis.