Copy number variation associated with Kallmann syndrome: new genetics insights from genome-wide studies.

Kallmann syndrome and normosmic isolated hypogonadotropic hypogonadism (IHH) are developmental disorders characterized by hypogonadotropic hypogonadism that, in the former case, is coupled to loss of the sense of smell. Linkage analyses, deletion mapping and candidate gene approaches uncovered several loci in the pathogenetic mechanism of these diseases (Figure 1). However, loss-of-function mutations in these genes account for only 30% of hypogonadotropic hypogonadism cases, suggesting that many disease-causing genes remain to be discovered. Copy number variations (CNVs) include inherited, de novo and somatically acquired deviations from a diploid state (deletions, duplications, insertions and complex genomic rearrangements) within a particular chromosomal segment. They usually are 1 kb in length or larger. Since the discovery of the important role of CNVs in human genome variability and also the recent development of high-resolution microarraybased technologies, a number of studies using these variants as genetic markers have emerged. Hence, CNVs are considered high risk factors for a considerable fraction of inherited and acquired diseases. In Asian Journal of Andrology, a recent report by Zhang et al. provided some evidence for the potential involvement of CNVs in Kallmann syndrome. The authors used the array technology to investigate the genomewide profile of structural variations in one consanguineous family with Kallmann syndrome. The results revealed that affected individuals had common CNVs (microdeletions) on five distinct chromosomal regions: 1p21.1, 2q32.2, 8q21.13, 14q21.2 and Xp22.31. Interestingly, the variant on Xp22.31 was found in an intronic region of KAL1, a gene responsible for X-linked form of Kallmann syndrome. Molecular testing for KAL1 (and also for FGFR1) was found to be normal, although alterations outside the exonic and splice site junction regions typically studied could not be excluded. In addition, genomic microdeletion in this Xp22.3 CNV was found in one of 29 Han Chinese sporadic Kallmann syndrome patients and in one of four other familial