Testicular Expressed Genes Are Missing in Familial X-Linked Kallmann Syndrome due to Two Large Different Deletions in Daughter’s X Chromosomes

Abstract

Background: X-linked Kallmann syndrome (KS) is caused mainly by point mutations, in the KAL1 gene. Large deletions >1 Mb are rare events in the human population and commonly result in contiguous gene syndromes. Methods: A search for the mutation causing KS carried out on two pairs of first-degree cousins of 2 sisters. Results: Two different apparently independent deletions were found. The deleted sequences encompass the KAL1 gene and four known additional genes exclusively expressed in testis. Two of these genes belong to the FAM9 gene family, which shares some homology with the SCYP3 gene, previously implicated in azoospermia. One of the events causing the deletion may have been mediated by an L1 transposition, the other by a non-homologous end joining. Such non-homologous recombinations have not yet been reported in the KAL genomic region and thus this area may be more prone to deletions than previously expected. Conclusions: This is the first report on genetic characterization of KS with a deletion of solely testis-expressed genes. The absence of these genes may have unfavorable implications for the patients regarding future fertility.

Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome

“…Notably, the breakpoint-flanking regions of this deletion contained Alu repeats but not palindromes or non-B motifs. In this regard, Hershkovitz et al [2008] reported that the NHEJ-induced deletion in their cases was accompanied by L1 repeats. Thus, MMBIR and NHEJ at Xp22.31 could be facilitated by repeat sequences independently of other rearrangement-inducing DNA features.…”

“…Conversely, NAHR is unlikely to be involved in other Xp22.31 microdeletions that are not associated with repetitive sequences. In 2008, Hershkovitz et al characterized the genomic structures of 2 ANOS1 -containing microdeletions harbored by members of the same family [Hershkovitz et al, 2008]. The breakpoints of these deletions shared no homology and had short nucleotide stretches at the fusion junctions, indicating that nonhomologous end-joining (NHEJ) underlies these copy number variations (CNVs) [Hershkovitz et al, 2008].…”