ESPE Abstracts

Background: Mutations in CHD7 cause a rare multi-organ system disorder, CHARGE syndrome (CS). Genital hypoplasia has been described in 60-80% of reported cases because of idiopathic hypogonadotropic hypogonadism (IHH), which is a result of inadequate GnRH secretion in the hypothalamus. Correspondingly, IHH and anosmia are expected in cases with CHD7 mutation. However, due to the phenotypic spectrum of CHD7, mutations have also been reported in IHH patients without typical CS features. Therefore, we aimed to identify CHD7 "uncertain significance" RSVs to expand the known spectrum in IHH patients who could not include in any CS classification.

Methods: RSVs in CHD7 were screened in anosmic and normosmic IHH patients without CS classification or criteria. Determined RSVs were evaluated according to ACMG/AMP standards. gnomAD was used to identify variants with MAF <0.01%. DANN score and pathogenicity were determined using VarSome and InterVar. "Pathogenic", "likely pathogenic" and "uncertain significance" classification criteria were evaluated and others excluded.

Results: Eight missense "uncertain significance" alterations (p.Arg459Cys, p.Gly1260Ser, p.Ala2733Thr, p.Asn785Ser, p.Arg886Trp, p.Ser559Leu, p.Asp2390Glu, and p.Pro515Ala) and one nonsense "pathogenic" variant (p.Gln61Ter) detected in CHD7 from nine unrelated IHH patients without CS criteria. Seven of nine patients had also IHH related gene variants including SEMA3E, WDR11, OTUD4, FGF17, FGFR1, PCSK1, RAB3GAP2, AXL, and PCSK1 in the heterozygous state.

Conclusion: Based on our data, RSVs of uncertain significance in CHD7 according to ACMG/AMP criteria may be associated with anosmic and normosmic IHH. The discovery of the increasing number of RSVs in CHD7 showed that this gene is becoming progressively prominent in the IHH. The RSVs ratio, which may be causal, in IHH-related genes has been found quite high in our cohort (77.7%). As a result of focused researches, it is known that novel genes are added to the list of genes responsible for oligogenic inheritance both anosmic and normosmic IHH. For these and similar reasons, we think that it is important not to ignore the missense variants in genes known to be usually disease-causing truncating mechanisms, such as CHD7. These findings confirm that CHD7 variants can lead to a broad spectrum of phenotypes, and suggest that the CHD7 product is required for the GnRH migration. Accordingly, patients with IHH phenotype should be examined for possible CHD7 mutations, even if they do not have CS characteristics. In addition, major and minor criteria of CHARGE syndrome should be further investigated if CHD7 mutations are detected to allow for more optimal patient management.