Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes

Abstract

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening.

Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations.

Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes.

Main outcome measures: Reproductive and nonreproductive phenotypes within each genetic group were measured.

Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors.

Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.

Figures

Figure 1.

Number of KS probands with rare sequence variants in each of the neurodevelopmental genetic groups studied.

Figure 2.

Pubertal severity at presentation in male KS probands. A, Individual values of TV at presentation in male probands within each gene/signaling group. Prepubertal TV less than 4 mL and pubertal TV of 4 mL or greater. KAL1, KAL1; FGF, FGF8/FGFR1 signaling pathway; PROK, PROK2/PROKR2 signaling pathway; CHD7, CHD7; Neg, gene–negative group; HS, HS6ST1. B, Comparison of individual TV at presentation between probands harboring KAL1 mutations (KAL1 group) vs probands who were negative for KAL1 mutations (non-KAL1 group). *P < .05

Figure 3.

Prevalence of nonreproductive phenotypes and their relative enrichment within specific genetic groups. Six panels show the relative enrichment of synkinesia (A), dental agenesis (B), hearing loss (C), syndactyly/camptodactyly/polydactyly (D), renal agenesis (E), and cleft lip/palate (F) within specific genetic groups. In each panel, 2 histograms are shown: the larger histogram shows the percentage of probands with RSVs in a specific gene compared with probands negative for the gene (eg, in panel A, KAL1 probands vs non-KAL1 probands and likewise in panels B–F). The unadjusted OR for the enrichment of the relevant phenotype within the specific genetic group is shown in the top right hand corner of the panel. The smaller histogram in each panel displays the absolute percentage of probands displaying the phenotype within each individual genetic group. CHD7, CHD7; FGF, FGF8/FGFR1 signaling pathway; KAL1, KAL1; Neg, gene-negative group; non-KAL1, all probands without KAL1 mutations; non-FGF, all probands without FGF8/FGFR1 mutations; non-CHD7, all probands without CHD7 mutations; PROK, PROK2/PROKR2 signaling pathway. *P < .05 for KAL1 vs non-KAL1 (A); FGF vs Non-FGF (B and D); CHD7 vs Non-CHD7 (C).

Figure 4.

Genetic signature(s) enriched within each phenotype expressed on the basis of strength of statistical association. Highly associated phenotypes represent features in which specific genetic mutations were enriched with statistical significance in this study (P < .05); Possibly associated phenotypes represent features in which no specific genes were enriched statistically in this study, but genes with either previously reported associations or with considerable prevalence of the relevant phenotypes are shown.