Kallmann Syndrome due to Balanced X Chromosomal Pericentric Inversion Disrupting ANOS1.

Background: Kallmann syndrome (KS) is a rare congenital disorder characterized by hypogonadotropic hypogonadism and anosmia/hyposmia. KS primarily results from nucleotide substitutions and copy number variations in known causative genes. Only one balanced X chromosomal inversion involving ANOS1 has been identified in a patient.

Methods: We encountered a boy with typical clinical features of KS. G-banding showed a 46,Y,inv(X)(pter→p22.32::q21.1→p22.32::q21.1→qter) karyotype, and whole genome sequencing and array-based comparative genomic hybridization detected a copy number neutral pericentric inversion involving a 72-Mb region. The breakpoints were mapped to ANOS1 intron 3 and an intergenic region at Xq21.1. The two breakpoints shared a 3-bp complementary sequence but were not associated with repetitive elements or nucleotide insertions at the fusion junction.

Conclusions: These results indicate that KS-causative inversions on the X chromosome can arise from replication-based errors. Furthermore, our data provide evidence that balanced X chromosomal inversions constitute a rare monogenic cause of KS.