Expanding the genetic spectrum of ANOS1 mutations in patients with congenital hypogonadotropic hypogonadism. 
What is the prevalence and functional consequence of ANOS1 (KAL1) mutations in a group of men with congenital hypogonadotropic hypogonadism (CHH)?  Three of forty-two (7.1%) patients presented ANOS1 mutations, including a novel splice site mutation leading to exon skipping and a novel contiguous gene deletion associated with ichthyosis.  CHH is characterized by lack of pubertal development and infertility, due to deficient production, secretion or action of GnRH, and can be associated with anosmia/hyposmia (Kallmann syndrome, KS) or with a normal sense of smell (normosmic CHH).  Mutations in the anosmin-1 (ANOS1) gene are responsible for the X-linked recessive form of KS.  This cross-sectional study included 42 unrelated men with CHH (20 with KS and 22 with normosmic CHH).  Patients were screened for mutations in the ANOS1 gene by DNA sequencing.  Identified mutations were further investigated by RT-PCR analysis and multiplex ligation-dependent probe amplification (MLPA) analysis.  Hemizygous mutations were identified in three (7.1%) KS cases: a novel splice acceptor site mutation (c.542-1G>C), leading to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing); a recurrent nonsense mutation (c.571C>T, p.Arg191*); and a novel 4.8 Mb deletion involving ANOS1 and eight other genes (VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X) in KS associated with ichthyosis.  Objective olfactory testing was not performed in all cases of self-reported normosmia and this may have underestimated the olfactory deficits.  This study further expands the spectrum of known genetic defects associated with CHH and suggests that patients with self-reported normal olfactory function should not be excluded from ANOS1 genetic testing.  This study was funded by the Portuguese Foundation for Science and Technology.  The authors have no conflicts of interest.  N/A.