Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses

Abstract

Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.

Fig. 1. Pedigree of a North American kindred, initially recruited as two independent families (probands PID V-1, VI-21) showing co-segregation of a novel pathogenic POU4F3 (c.37del) variant and autosomal dominant sensorineural hearing loss.

A Seven-generation pedigree with 38 direct descendants of the pedigree founders with hearing loss are marked with a black symbol. B Electropherogram of the novel POU4F3 c.37del frame-shifting variant (left panel, bottom) compared to reference sequence (left panel, top) and to an unaffected relative (right panel, bottom) compared to reference sequence (right panel, top). PID person ID in the pedigree.

Fig. 2. Decade-wise audiograms for POU4F3 c.37delC carriers in the North American kindred show variability in progression and severity.

Each POU4F3 c.37delC carrier is represented by a unique colored line to track hearing loss progression. The unique PID (plus number of audiograms) is provided to the right of each graphic margin. The text box (bottom left) in each graphic gives the number (N) of POU4F3 c.37delC carriers and the total number of audiograms that were available per decade. Only a subset of POU4F3 c.37delC carriers have audiograms for each decade.

Fig. 3. Longitudinal linear regression analyses of pure tone hearing thresholds for eight affected POU4F3 c.37del carriers.

Each panel provides serial pure tone air conduction thresholds as a function of age, and longitudinal linear regression results at each octave frequency from 0.25–8 kHz; right and left ear results are shown separately.

Fig. 4. Comparison of age-related typical audiograms (ARTAs) across four DFNA15/POU4F3 pedigrees.

A ARTA for the North American kindred range from the 1st to 8th decade including all POU4F3 c.37del carriers (17 clinically affected including 3 with normal hearing). B ARTA for the 14 clinically affected c.37del carriers. C ARTA from a Dutch family with the L223P variant. D ARTA for a Dutch family with the L289F variant. E Israeli Jewish family with the 884del8 variant. All analyses are based on original threshold data without correction for presbycusis. ARTAs adapted from this figure (de Heer et al. [11]) with permission.